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The C. elegans gene phb-1 (ORF Y37E3.9; UniProt Q9BKU4) encodes mitochondrial prohibitin complex protein 1 (PHB-1), a 32 kDa protein belonging to the evolutionarily conserved prohibitin family and the broader SPFH (stomatin/prohibitin/flotillin/HflK/C) superfamily of membrane scaffold proteins (artalsanz2009prohibitinandmitochondrial pages 1-2, artalsanz2009prohibitinandmitochondrial pages 4-5). PHB-1 contains a conserved PHB/Band_7 (SPFH) domain adjacent to an N-terminal hydrophobic membrane-anchoring region, and a C-terminal coiled-coil domain that mediates heterodimerization with PHB-2 (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 1-2). Both PHB-1 and PHB-2 subunits are ubiquitously and abundantly expressed in C. elegans tissues and are interdependent: depletion of either subunit results in the absence of the functional complex (artalsanz2009prohibitinandmitochondrial pages 1-2, artalsanz2009prohibitinandmitochondrial pages 2-3).
The following table summarizes the key attributes of PHB-1:
| Attribute | Summary |
|---|---|
| Protein name | Mitochondrial prohibitin complex protein 1; Prohibitin-1 (PHB-1) (artalsanz2009prohibitinandmitochondrial pages 1-2, hernandorodriguez2018mitochondrialqualitycontrol pages 8-10) |
| Gene name | phb-1; ORF Y37E3.9 (verified against UniProt target specification; functional literature on C. elegans prohibitin complex is consistent with this identity) (artalsanz2009prohibitinandmitochondrial pages 1-2, artalsanz2009prohibitinandmitochondrial pages 2-3) |
| UniProt ID | Q9BKU4 (from target specification; literature supports the corresponding C. elegans prohibitin-1 identity and function) (artalsanz2009prohibitinandmitochondrial pages 1-2, artalsanz2009prohibitinandmitochondrial pages 2-3) |
| Organism | Caenorhabditis elegans (artalsanz2009prohibitinandmitochondrial pages 3-4, hernandorodriguez2018mitochondrialqualitycontrol pages 8-10) |
| Protein family | Prohibitin family; member of the SPFH/Band_7 superfamily of membrane scaffold proteins (artalsanz2009prohibitinandmitochondrial pages 4-5, hernandorodriguez2018mitochondrialqualitycontrol pages 8-10) |
| Key domains | Conserved PHB/SPFH (Band_7) domain with N-terminal hydrophobic/transmembrane anchor and C-terminal coiled-coil region mediating PHB-1/PHB-2 assembly (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 1-2) |
| Molecular weight | PHB-1 is ~32 kDa; PHB-2 is ~34 kDa (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 1-2) |
| Subcellular localization | Predominantly mitochondrial inner membrane (IMM), with the complex projecting into the intermembrane space/crista lumen; localization within crista-associated membrane regions is implicated in membrane organization (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, hernandorodriguez2018mitochondrialqualitycontrol pages 10-12, lange2025insituarchitecture pages 2-3) |
| Complex partners | Obligatory heterocomplex with PHB-2; functionally associated with m-AAA proteases, OXPHOS/ATP synthase components, OPA1/cristae machinery, ATAD3/nucleoid-associated factors, and lipid homeostasis pathways (hernandorodriguez2018mitochondrialqualitycontrol pages 16-17, hernandorodriguez2018mitochondrialqualitycontrol pages 8-10) |
| Complex stoichiometry | In C. elegans and earlier models, a ~1 MDa ring-like assembly of ~12–16 PHB-1/PHB-2 heterodimers was proposed; recent in situ human cryo-ET instead resolved a bell-shaped 11-subunit alternating PHB1/PHB2 assembly, refining structural understanding of prohibitin scaffolds (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 1-2, lange2025insituarchitecture pages 4-7, lange2025insituarchitecture pages 1-2) |
| Primary molecular function | Membrane-bound scaffold/chaperone rather than enzyme or transporter; stabilizes newly synthesized/assembled IMM proteins, cooperates with m-AAA proteases in membrane protein quality control, helps organize lipid microenvironments, and supports cristae architecture and respiratory chain integrity (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 4-5, artalsanz2009prohibitinandmitochondrial pages 3-4, artalsanz2009prohibitinandmitochondrial pages 2-3) |
| Key signaling pathway interactions: IIS/DAF-2 | PHB depletion shortens lifespan in wild type but extends lifespan in metabolically compromised animals such as daf-2 mutants; PHB influences lipid remodeling, TAG/yolk homeostasis, and ER stress in an insulin-signaling-dependent manner (lourenco2021themitochondrialprohibitin pages 3-5, lourenco2021themitochondrialprohibitin pages 5-7, lourenco2021themitochondrialprohibitin pages 2-3) |
| Key signaling pathway interactions: TORC2/SGK-1 | SGK-1 is a major downstream determinant of the prohibitin longevity phenotype; PHB depletion extends lifespan in sgk-1 and rict-1 mutants, suppresses their mitochondrial and lipogenesis defects, and functionally links PHB to mTORC2-SGK-1 control of mitochondrial homeostasis (cruz‐ruiz2021prohibitindepletionextends pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 8-10, cruz‐ruiz2021prohibitindepletionextends pages 2-4, cruz‐ruiz2021prohibitindepletionextends pages 13-14) |
| Key signaling pathway interactions: UPRmt/ATFS-1 | PHB depletion robustly induces the mitochondrial unfolded protein response (UPRmt) in wild type; UPRmt behavior is context dependent in IIS/TORC2 mutants, and ATFS-1-dependent mitochondrial stress signaling contributes to longevity outcomes in PHB-deficient backgrounds (artalsanz2009prohibitinandmitochondrial pages 5-7, fernandezabascal2023twoconservedtranscription pages 4-7, fernandezabascal2023twoconservedtranscription pages 1-4, cruz‐ruiz2021prohibitindepletionextends pages 1-2) |
| Lifespan effects | Depletion of prohibitin shortens wild-type lifespan but extends lifespan in several metabolically compromised backgrounds including daf-2, sgk-1, and rict-1 mutants; this is one of the defining context-dependent phenotypes of the PHB complex in C. elegans aging biology (lourenco2021themitochondrialprohibitin pages 2-3, cruz‐ruiz2021prohibitindepletionextends pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 2-3) |
| Essential cellular processes | Embryonic viability, germline function, mitochondrial morphogenesis, cristae maintenance, respiratory chain/OXPHOS biogenesis, mitochondrial proteostasis, lipid homeostasis, nucleoid/mtDNA organization, and mitochondrial quality control; PHB-2 additionally serves as an IMM mitophagy receptor via LC3 interaction, whereas PHB-1 participates in the heterocomplex that supports these functions (artalsanz2009prohibitinandmitochondrial pages 3-4, hernandorodriguez2018mitochondrialqualitycontrol pages 16-17, hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, wei2017prohibitin2is pages 1-3) |
Table: This table summarizes the core identity, localization, molecular role, pathway interactions, and phenotypic consequences of PHB-1/prohibitin-1 in C. elegans. It is useful as a compact reference linking the prohibitin complex’s structural role in mitochondria to its context-dependent effects on metabolism, stress signaling, and longevity.
PHB-1 and PHB-2 associate to form a large, ring-like macromolecular complex of approximately 1 MDa at the mitochondrial inner membrane (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 1-2). Earlier biochemical studies estimated that this complex consists of 12–16 PHB-1/PHB-2 heterodimeric building blocks with a diameter of 20–25 nm (artalsanz2009prohibitinandmitochondrial pages 1-2, artalsanz2009prohibitinandmitochondrial pages 3-4). PHB-1 is anchored at the membrane surface via its N-terminal hydrophobic region, while PHB-2 contains a true transmembrane domain (artalsanz2009prohibitinandmitochondrial pages 1-2).
A landmark structural advance was reported by Lange et al. (2025), who used cryo-electron tomography and subtomogram averaging to determine the in situ architecture of the human prohibitin complex within intact mitochondria. This study revealed a bell-shaped structure consisting of 11 alternating PHB1 and PHB2 molecules (either 6PHB1/5PHB2 or 5PHB1/6PHB2), with a diameter of approximately 190 Å and a height of 84 Å (lange2025insituarchitecture pages 4-7, lange2025insituarchitecture pages 1-2). The N-terminal transmembrane domains anchor the complex in the lipid bilayer, while the C-terminal coiled-coil domains converge at the top of the bell through electrostatic interactions (lange2025insituarchitecture pages 4-7). The study further revealed an average of approximately 43 prohibitin complexes per crista, covering 1–3% of the cristae membrane surface (lange2025insituarchitecture pages 1-2). These structures are enriched at crista membranes and project toward the intermembrane space/crista lumen (lange2025insituarchitecture pages 2-3). This revised stoichiometry (11 subunits rather than 12–16 heterodimers) refines our understanding of prohibitin architecture, though the C. elegans complex stoichiometry has not been independently resolved at this level.
PHB-1 localizes primarily to the inner mitochondrial membrane (IMM), where the complex projects into the intermembrane space (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, hernandorodriguez2018mitochondrialqualitycontrol pages 10-12, lange2025insituarchitecture pages 2-3). The complex is part of the ER-mitochondria organizing network (ERMIONE), which links the endoplasmic reticulum and both mitochondrial membranes to maintain membrane architecture and homeostasis (hernandorodriguez2018mitochondrialqualitycontrol pages 10-12). PHB-1 has also been reported to interact transiently with peroxisomal and lipid droplet proteins, though its predominant site of action is the IMM (hernandorodriguez2018mitochondrialqualitycontrol pages 10-12). In C. elegans, PHB-1 and PHB-2 are particularly required in tissues with high energy demands and actively proliferating cells, including the germline and body-wall muscle (artalsanz2009prohibitinandmitochondrial pages 3-4).
PHB-1 is not an enzyme, transporter, or signaling receptor. Rather, it functions as a membrane-bound scaffold and holdase/unfoldase-type chaperone within the inner mitochondrial membrane (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 4-5, artalsanz2009prohibitinandmitochondrial pages 3-4). Its precise biochemical activity has remained challenging to define, but converging evidence supports several interrelated functions:
PHB-1 physically interacts with mitochondrial m-AAA proteases (including SPG7 and AFG3L1/2) and modulates their activity (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, hernandorodriguez2018mitochondrialqualitycontrol pages 16-17). The PHB complex protects newly imported and newly synthesized OXPHOS subunits—particularly the highly hydrophobic mitochondrial-encoded subunits of complexes I and IV—from premature protease-mediated degradation, acting as a holdase-type chaperone until proper assembly with nuclear-encoded counterparts can occur (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 4-5, artalsanz2009prohibitinandmitochondrial pages 3-4). PHB-1 also associates with ATP synthase subunits, and its loss affects respiratory supercomplex formation (hernandorodriguez2018mitochondrialqualitycontrol pages 16-17, lourenco2021themitochondrialprohibitin pages 12-13).
The PHB complex stabilizes long isoforms of OPA1 (the C. elegans ortholog is EAT-3), which are essential for mitochondrial inner membrane fusion and cristae junction formation (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, hernandorodriguez2018mitochondrialqualitycontrol pages 16-17, artalsanz2009prohibitinandmitochondrial pages 4-5). Loss of prohibitins leads to aberrant OPA1 processing, disrupted cristae architecture, and severe mitochondrial fragmentation—transforming normal tubular elongated mitochondria into fragmented structures, as observed in C. elegans body-wall muscle (artalsanz2009prohibitinandmitochondrial pages 3-4, hernandorodriguez2018mitochondrialqualitycontrol pages 8-10). PHB keeps the OMA1 protease in check; loss of PHB releases OMA1 to cleave OPA1 into short isoforms, driving fragmentation (artalsanz2009prohibitinandmitochondrial pages 2-3).
PHB-1 functions as a membrane organizer that clusters specific lipids at defined sites within the IMM. Genetic and biochemical evidence demonstrates interactions between prohibitins and the metabolism of cardiolipin and phosphatidylethanolamine (PE), two key mitochondrial phospholipids (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, hernandorodriguez2018mitochondrialqualitycontrol pages 16-17). Loss of PHB complexes alters cardiolipin acylation and affects cholesterol biosynthesis, linking prohibitin to membrane lipid homeostasis (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10). The PHB/SPFH domain itself may mediate lipid binding, though this has not been definitively demonstrated biochemically (artalsanz2009prohibitinandmitochondrial pages 4-5).
PHB-1 associates with mitochondrial nucleoids, the protein-DNA complexes that package mtDNA, together with TFAM, mtSSB, and ATAD3 (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10). Both PHB subunits co-purify with tagged mitochondrial DNA-binding proteins, and depletion of either PHB or ATAD3 dramatically reduces mitochondrial protein synthesis (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10). In mouse neurons, loss of PHB2 destabilizes the mitochondrial genome and leads to respiratory deficiencies, demonstrating that prohibitin scaffolds are required for mtDNA maintenance (hernandorodriguez2018mitochondrialqualitycontrol pages 16-17, lourenco2021themitochondrialprohibitin pages 12-13).
While PHB-1 itself does not directly bind LC3, its obligate partner PHB-2 has been identified as an inner mitochondrial membrane mitophagy receptor. PHB-2 binds LC3-II through an LC3-interacting region (LIR) motif upon proteasome-dependent rupture of the outer mitochondrial membrane, facilitating Parkin-mediated mitophagy (wei2017prohibitin2is pages 12-13, wei2017prohibitin2is pages 1-3, wei2017prohibitin2is pages 4-5). PHB-1 interacts with LC3-II indirectly through the PHB-1/PHB-2 complex (lahiri2017phb2prohibitin2an pages 1-2). In C. elegans, PHB-2 is essential for clearing paternal mitochondria during embryogenesis, contributing to maternal mitochondrial inheritance (wei2017prohibitin2is pages 12-13, qi2023essentialproteinphb2 pages 5-6). A PINK1-dependent pathway involving PARL and PGAM5 further connects the PHB complex to mitophagy regulation (qi2023essentialproteinphb2 pages 5-6, belser2021roleofprohibitins pages 1-2).
In C. elegans, homozygous phb-1 and phb-2 deletion mutants are embryonic lethal; animals that develop from heterozygous mothers (due to maternal contribution of PHB protein) grow into sterile adults with severely compromised germline function and strongly induced mitochondrial unfolded protein response (UPRmt) (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, hernandorodriguez2018mitochondrialqualitycontrol pages 16-17). Post-embryonic depletion impairs germline function with reduced oocyte production (artalsanz2009prohibitinandmitochondrial pages 3-4).
One of the most striking and extensively studied phenotypes of PHB-1 is its paradoxical, context-dependent effect on lifespan. PHB depletion shortens the lifespan of wild-type C. elegans but dramatically extends the lifespan of metabolically compromised mutants, including insulin/IGF-1 signaling (IIS) receptor daf-2 mutants, TORC2 pathway mutants sgk-1 and rict-1, and dietary-restricted animals (fernandezabascal2023twoconservedtranscription pages 4-7, lourenco2021themitochondrialprohibitin pages 2-3, cruz‐ruiz2021prohibitindepletionextends pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 2-3). This paradox has been a major focus of C. elegans* aging research and is summarized in the table below:
| Genetic Background | Lifespan Effect of PHB Depletion | UPRmt Response | Mechanism/Notes | Key Reference |
|---|---|---|---|---|
| Wild-type | Shortens lifespan (fernandezabascal*2023twoconservedtranscription pages 4-7, lourenco2021themitochondrialprohibitin pages 5-7, lourenco2021themitochondrialprohibitin pages 2-3, gatsi2014prohibitinmediatedlifespanand pages 1-2) | Strongly induced (fernandezabascal2023twoconservedtranscription pages 4-7, fernandezabascal2023twoconservedtranscription pages 1-4, artalsanz2009prohibitinandmitochondrial pages 5-7) | PHB loss disrupts mitochondrial membrane organization and proteostasis, induces mitochondrial stress, and is generally detrimental in metabolically normal animals (hernandorodriguez2018mitochondrialqualitycontrol pages 8-10, artalsanz2009prohibitinandmitochondrial pages 4-5) | Gatsi et al. 2014; Fernández-Abascal et al. 2025; Lourenço & Artal-Sanz 2021 (fernandezabascal*2023twoconservedtranscription pages 4-7, lourenco2021themitochondrialprohibitin pages 2-3, gatsi2014prohibitinmediatedlifespanand pages 1-2) |
| daf-2(e1370) | Extends lifespan (fernandezabascal*2023twoconservedtranscription pages 4-7, lourenco2021themitochondrialprohibitin pages 5-7, lourenco2021themitochondrialprohibitin pages 2-3, gatsi2014prohibitinmediatedlifespanand pages 1-2) | Suppressed/attenuated relative to PHB-depleted wild type (fernandezabascal2023twoconservedtranscription pages 4-7, fernandezabascal2023twoconservedtranscription pages 1-4, gatsi2014prohibitinmediatedlifespanand pages 1-2) | Canonical example of context dependence: defective IIS buffers some PHB-loss consequences; longevity links to altered lipid/energy metabolism and requires mitochondrial stress signaling components including ATFS-1 in recent work (fernandezabascal*2023twoconservedtranscription pages 4-7, lourenco2021themitochondrialprohibitin pages 3-5, lourenco2021themitochondrialprohibitin pages 5-7) | Gatsi et al. 2014; Fernández-Abascal et al. 2025; Lourenço & Artal-Sanz 2021 (fernandezabascal*2023twoconservedtranscription pages 4-7, lourenco2021themitochondrialprohibitin pages 3-5, gatsi2014prohibitinmediatedlifespanand pages 1-2) |
| sgk-1(ok538) | Extends lifespan (reported ~18% in one study) (cruz‐ruiz2021prohibitindepletionextends pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 3-4, gatsi2014prohibitinmediatedlifespanand pages 2-3) | Induced in sgk-1 mutants, but PHB depletion-associated longevity is accompanied by suppressed UPRmt relative to PHB-depleted wild type; later work also shows lifespan extension requires UPRmt and autophagy (gatsi2014prohibitinmediatedlifespanand pages 1-2, cruz‐ruiz2021prohibitindepletionextends pages 2-4) | PHB depletion suppresses sgk-1 mitochondrial, lipogenesis, yolk/lipoprotein, ROS, and oxygen-consumption defects; indicates strong interaction with TORC2/SGK-1 and membrane-lipid homeostasis (cruz‐ruiz2021prohibitindepletionextends pages 1-2, cruz‐ruiz2021prohibitindepletionextends pages 2-4, cruz‐ruiz2021prohibitindepletionextends pages 13-14) | Gatsi et al. 2014; de la Cruz-Ruiz et al. 2021 (cruz‐ruiz2021prohibitindepletionextends pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 1-2, cruz‐ruiz2021prohibitindepletionextends pages 2-4) |
| rict-1(ft7) | Extends lifespan (gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 2-3) | UPRmt regulation parallels sgk-1; rict-1 loss suppresses PHB depletion-associated UPRmt and interacts with SGK-1 in a pathway parallel to DAF-2 (gatsi2014prohibitinmediatedlifespanand pages 8-10, gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 2-3) | Supports model that mTORC2/RICT-1-SGK-1 signaling is a major determinant of whether PHB depletion is pro- or anti-longevity (gatsi2014prohibitinmediatedlifespanand pages 8-10, gatsi2014prohibitinmediatedlifespanand pages 6-8, gatsi2014prohibitinmediatedlifespanand pages 2-3) | Gatsi et al. 2014 (gatsi2014prohibitinmediatedlifespanand pages 8-10, gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 2-3) |
| Dietary restricted animals | Extends lifespan (lourenco2021themitochondrialprohibitin pages 2-3) | Not specified directly in the cited review excerpt (lourenco2021themitochondrialprohibitin pages 2-3) | Lourenço & Artal-Sanz summarize that PHB depletion can extend lifespan in dietary restriction contexts, reinforcing that PHB effects depend on systemic metabolic state rather than PHB acting as a simple pro- or anti-aging factor (lourenco2021themitochondrialprohibitin pages 2-3, lourenco2021themitochondrialprohibitin pages 7-8) | Lourenço & Artal-Sanz 2021 (lourenco2021themitochondrialprohibitin pages 2-3, lourenco2021themitochondrialprohibitin pages 7-8) |
Table: This table summarizes how prohibitin depletion has opposite effects on lifespan depending on the C. elegans genetic or metabolic background. It is useful for quickly comparing longevity outcomes, UPRmt behavior, and the major mechanistic interpretations across key studies.
PHB functionally interacts with the IIS pathway at multiple levels. Among the three kinases downstream of DAF-2 (the insulin/IGF-1 receptor), only loss of SGK-1 recapitulates the lifespan extension observed in daf-2 mutants upon PHB depletion (gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 3-4). PHB depletion in daf-2 mutants extends lifespan while attenuating the UPRmt, suggesting a mitochondrial threshold effect where reduced insulin signaling protects against the deleterious consequences of PHB loss (fernandezabascal2023twoconservedtranscription pages 4-7, fernandezabascal2023twoconservedtranscription pages 1-4). PHB depletion also alters glycerolipid and triacylglyceride (TAG) pools in an IIS-dependent manner (lourenco2021themitochondrialprohibitin pages 3-5).
SGK-1 receives input from RICT-1/mTORC2, and both operate in a pathway parallel to DAF-2 for the PHB-mediated lifespan phenotype (gatsi2014prohibitinmediatedlifespanand pages 8-10, gatsi2014prohibitinmediatedlifespanand pages 1-2, gatsi2014prohibitinmediatedlifespanand pages 2-3). sgk-1 mutants exhibit impaired mitochondrial homeostasis, lipogenesis, and yolk formation due to membrane lipid and sterol homeostasis alterations; remarkably, all these defects are suppressed by PHB depletion (cruz‐ruiz2021prohibitindepletionextends pages 1-2). PHB depletion in sgk-1 mutants normalizes mitochondrial size, reduces excessive oxygen consumption and ROS levels, and restores mitochondrial morphology from abnormally swollen to normal architecture (cruz‐ruiz2021prohibitindepletionextends pages 2-4). The lifespan extension in sgk-1 mutants upon PHB depletion requires both the UPRmt and autophagy, but not mitophagy (cruz‐ruiz2021prohibitindepletionextends pages 1-2, cruz‐ruiz2021prohibitindepletionextends pages 2-4). The lipid metabolism transcription factor SREBP1/SBP-1 is also required for lifespan extension (cruz‐ruiz2021prohibitindepletionextends pages 1-2).
PHB depletion is a potent inducer of the UPRmt in wild-type animals, activating mitochondrial chaperone genes such as hsp-6 through the transcription factor ATFS-1 (artalsanz2009prohibitinandmitochondrial pages 4-5, artalsanz2009prohibitinandmitochondrial pages 5-7, fernandezabascal2023twoconservedtranscription pages 4-7, fernandezabascal2023twoconservedtranscription pages 1-4, gatsi2014prohibitinmediatedlifespanand pages 8-10). However, the relationship between UPRmt induction and lifespan is complex: in daf-2 mutants, PHB depletion extends lifespan while paradoxically attenuating the UPRmt relative to PHB-depleted wild type (fernandezabascal2023twoconservedtranscription pages 4-7, fernandezabascal2023twoconservedtranscription pages 1-4). A recent genome-wide double RNAi screen identified two new transcription factors, ZNF-622 and TLF-1, as specific regulators of the PHB-mediated mitochondrial stress response, as well as the histone deubiquitinase USP-48 as a differential modulator of the UPRmt and aging in wild-type versus IIS mutant backgrounds (fernandezabascal*2023twoconservedtranscription pages 4-7).
PHB modulates fat content and fatty acid composition, with a trend toward increased shorter/monounsaturated fatty acids and decreased longer/polyunsaturated fatty acids upon PHB depletion (lourenco2021themitochondrialprohibitin pages 2-3). The complex also regulates sphingolipids (sphingomyelin, ceramide) and glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine) in a genetic background-dependent manner (lourenco2021themitochondrialprohibitin pages 2-3). PHB depletion affects carbohydrate and amino acid metabolism, the TCA cycle, and trehalose accumulation, demonstrating broad effects on the C. elegans metabolic network (lourenco2021themitochondrialprohibitin pages 5-7). PHB interacts with the fat mobilization regulator NHR-49 and the fatty acid desaturase FAT-7 (lourenco2021themitochondrialprohibitin pages 7-8). PHB depletion also induces ER stress in wild-type worms, but daf-2 mutants are protected from this ER stress, providing a mechanistic link between PHB, mitochondrial function, ER homeostasis, and IIS signaling (lourenco2021themitochondrialprohibitin pages 3-5, lourenco2021themitochondrialprohibitin pages 5-7).
Prohibitins are among the most highly conserved eukaryotic proteins, with orthologs in yeast, nematodes, insects, and mammals sharing both structural organization and core functions (artalsanz2009prohibitinandmitochondrial pages 1-2, artalsanz2009prohibitinandmitochondrial pages 4-5). The PHB/SPFH domain, the coiled-coil assembly region, and the ring-like supramolecular architecture are conserved features. Cross-species functional complementation experiments demonstrate that Plasmodium falciparum PHBs can complement yeast PHB mutants, underscoring deep functional conservation (artalsanz2009prohibitinandmitochondrial pages 4-5). The recently resolved in situ structure of human prohibitin (bell-shaped, 11 subunits) provides the first high-resolution architectural framework for understanding how prohibitin scaffolds organize the inner mitochondrial membrane across species (lange2025insituarchitecture pages 4-7, lange2025insituarchitecture pages 1-2).
PHB-1 in C. elegans is a non-enzymatic, inner mitochondrial membrane scaffold protein that forms an obligate complex with PHB-2. The PHB complex functions as a holdase/chaperone, lipid organizer, and structural scaffold essential for cristae morphogenesis, OXPHOS complex biogenesis, mitochondrial nucleoid stability, and membrane protein quality control. PHB-1 is essential for embryonic development and germline function. Its depletion induces the UPRmt and, depending on the metabolic state of the animal, either shortens or extends lifespan. The complex sits at a central nexus of nutrient-sensing pathways (IIS/DAF-2, TORC2/SGK-1) and mitochondrial stress responses (UPRmt/ATFS-1), modulating lipid metabolism, energy homeostasis, and aging in a context-dependent manner. Through its partner PHB-2, the complex also participates in mitophagy as an inner membrane receptor for LC3. The prohibitin complex thus represents one of the most functionally integrated mitochondrial regulatory assemblies studied in C. elegans biology.
References
(artalsanz2009prohibitinandmitochondrial pages 1-2): Marta Artal-Sanz and Nektarios Tavernarakis. Prohibitin and mitochondrial biology. Trends in Endocrinology & Metabolism, 20:394-401, Oct 2009. URL: https://doi.org/10.1016/j.tem.2009.04.004, doi:10.1016/j.tem.2009.04.004. This article has 363 citations and is from a domain leading peer-reviewed journal.
(artalsanz2009prohibitinandmitochondrial pages 4-5): Marta Artal-Sanz and Nektarios Tavernarakis. Prohibitin and mitochondrial biology. Trends in Endocrinology & Metabolism, 20:394-401, Oct 2009. URL: https://doi.org/10.1016/j.tem.2009.04.004, doi:10.1016/j.tem.2009.04.004. This article has 363 citations and is from a domain leading peer-reviewed journal.
(hernandorodriguez2018mitochondrialqualitycontrol pages 8-10): Blanca Hernando-Rodríguez and Marta Artal-Sanz. Mitochondrial quality control mechanisms and the phb (prohibitin) complex. Cells, Nov 2018. URL: https://doi.org/10.3390/cells7120238, doi:10.3390/cells7120238. This article has 93 citations.
(artalsanz2009prohibitinandmitochondrial pages 2-3): Marta Artal-Sanz and Nektarios Tavernarakis. Prohibitin and mitochondrial biology. Trends in Endocrinology & Metabolism, 20:394-401, Oct 2009. URL: https://doi.org/10.1016/j.tem.2009.04.004, doi:10.1016/j.tem.2009.04.004. This article has 363 citations and is from a domain leading peer-reviewed journal.
(artalsanz2009prohibitinandmitochondrial pages 3-4): Marta Artal-Sanz and Nektarios Tavernarakis. Prohibitin and mitochondrial biology. Trends in Endocrinology & Metabolism, 20:394-401, Oct 2009. URL: https://doi.org/10.1016/j.tem.2009.04.004, doi:10.1016/j.tem.2009.04.004. This article has 363 citations and is from a domain leading peer-reviewed journal.
(hernandorodriguez2018mitochondrialqualitycontrol pages 10-12): Blanca Hernando-Rodríguez and Marta Artal-Sanz. Mitochondrial quality control mechanisms and the phb (prohibitin) complex. Cells, Nov 2018. URL: https://doi.org/10.3390/cells7120238, doi:10.3390/cells7120238. This article has 93 citations.
(lange2025insituarchitecture pages 2-3): Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, and Stefan Jakobs. In situ architecture of the human prohibitin complex. Nature Cell Biology, 27:633-640, Mar 2025. URL: https://doi.org/10.1038/s41556-025-01620-1, doi:10.1038/s41556-025-01620-1. This article has 39 citations and is from a highest quality peer-reviewed journal.
(hernandorodriguez2018mitochondrialqualitycontrol pages 16-17): Blanca Hernando-Rodríguez and Marta Artal-Sanz. Mitochondrial quality control mechanisms and the phb (prohibitin) complex. Cells, Nov 2018. URL: https://doi.org/10.3390/cells7120238, doi:10.3390/cells7120238. This article has 93 citations.
(lange2025insituarchitecture pages 4-7): Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, and Stefan Jakobs. In situ architecture of the human prohibitin complex. Nature Cell Biology, 27:633-640, Mar 2025. URL: https://doi.org/10.1038/s41556-025-01620-1, doi:10.1038/s41556-025-01620-1. This article has 39 citations and is from a highest quality peer-reviewed journal.
(lange2025insituarchitecture pages 1-2): Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, and Stefan Jakobs. In situ architecture of the human prohibitin complex. Nature Cell Biology, 27:633-640, Mar 2025. URL: https://doi.org/10.1038/s41556-025-01620-1, doi:10.1038/s41556-025-01620-1. This article has 39 citations and is from a highest quality peer-reviewed journal.
(lourenco2021themitochondrialprohibitin pages 3-5): Artur B. Lourenço and Marta Artal-Sanz. The mitochondrial prohibitin (phb) complex in c. elegans metabolism and ageing regulation. Metabolites, 11:636, Sep 2021. URL: https://doi.org/10.3390/metabo11090636, doi:10.3390/metabo11090636. This article has 16 citations.
(lourenco2021themitochondrialprohibitin pages 5-7): Artur B. Lourenço and Marta Artal-Sanz. The mitochondrial prohibitin (phb) complex in c. elegans metabolism and ageing regulation. Metabolites, 11:636, Sep 2021. URL: https://doi.org/10.3390/metabo11090636, doi:10.3390/metabo11090636. This article has 16 citations.
(lourenco2021themitochondrialprohibitin pages 2-3): Artur B. Lourenço and Marta Artal-Sanz. The mitochondrial prohibitin (phb) complex in c. elegans metabolism and ageing regulation. Metabolites, 11:636, Sep 2021. URL: https://doi.org/10.3390/metabo11090636, doi:10.3390/metabo11090636. This article has 16 citations.
(cruz‐ruiz2021prohibitindepletionextends pages 1-2): Patricia de la Cruz‐Ruiz, Blanca Hernando‐Rodríguez, Mercedes M. Pérez‐Jiménez, María Jesús Rodríguez‐Palero, Manuel D. Martínez‐Bueno, Antoni Pla, Roxani Gatsi, and Marta Artal‐Sanz. Prohibitin depletion extends lifespan of a torc2/sgk‐1 mutant through autophagy and the mitochondrial upr. Aging Cell, May 2021. URL: https://doi.org/10.1111/acel.13359, doi:10.1111/acel.13359. This article has 22 citations and is from a domain leading peer-reviewed journal.
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(cruz‐ruiz2021prohibitindepletionextends pages 2-4): Patricia de la Cruz‐Ruiz, Blanca Hernando‐Rodríguez, Mercedes M. Pérez‐Jiménez, María Jesús Rodríguez‐Palero, Manuel D. Martínez‐Bueno, Antoni Pla, Roxani Gatsi, and Marta Artal‐Sanz. Prohibitin depletion extends lifespan of a torc2/sgk‐1 mutant through autophagy and the mitochondrial upr. Aging Cell, May 2021. URL: https://doi.org/10.1111/acel.13359, doi:10.1111/acel.13359. This article has 22 citations and is from a domain leading peer-reviewed journal.
(cruz‐ruiz2021prohibitindepletionextends pages 13-14): Patricia de la Cruz‐Ruiz, Blanca Hernando‐Rodríguez, Mercedes M. Pérez‐Jiménez, María Jesús Rodríguez‐Palero, Manuel D. Martínez‐Bueno, Antoni Pla, Roxani Gatsi, and Marta Artal‐Sanz. Prohibitin depletion extends lifespan of a torc2/sgk‐1 mutant through autophagy and the mitochondrial upr. Aging Cell, May 2021. URL: https://doi.org/10.1111/acel.13359, doi:10.1111/acel.13359. This article has 22 citations and is from a domain leading peer-reviewed journal.
(artalsanz2009prohibitinandmitochondrial pages 5-7): Marta Artal-Sanz and Nektarios Tavernarakis. Prohibitin and mitochondrial biology. Trends in Endocrinology & Metabolism, 20:394-401, Oct 2009. URL: https://doi.org/10.1016/j.tem.2009.04.004, doi:10.1016/j.tem.2009.04.004. This article has 363 citations and is from a domain leading peer-reviewed journal.
(fernandezabascal2023twoconservedtranscription pages 4-7): Jesús Fernandez-Abascal, Blanca Hernando-Rodríguez*, María Jesús Rodríguez-Palero, Aitor Jarit-Cabanillas, Manuel D. Martínez-Bueno, Mercedes M. Pérez-Jiménez, Enrique J. Clavijo-Bernal, Aitana Cambón, Ildefonso Cases, and Marta Artal-Sanz. Two conserved transcription factors and a histone deubiquitinase regulate the mitochondrial unfolded protein response and longevity interacting with insulin signalling. Unknown journal, Oct 2025. URL: https://doi.org/10.21203/rs.3.rs-3337719/v1, doi:10.21203/rs.3.rs-3337719/v1.
(fernandezabascal2023twoconservedtranscription pages 1-4): Jesús Fernandez-Abascal, Blanca Hernando-Rodríguez*, María Jesús Rodríguez-Palero, Aitor Jarit-Cabanillas, Manuel D. Martínez-Bueno, Mercedes M. Pérez-Jiménez, Enrique J. Clavijo-Bernal, Aitana Cambón, Ildefonso Cases, and Marta Artal-Sanz. Two conserved transcription factors and a histone deubiquitinase regulate the mitochondrial unfolded protein response and longevity interacting with insulin signalling. Unknown journal, Oct 2025. URL: https://doi.org/10.21203/rs.3.rs-3337719/v1, doi:10.21203/rs.3.rs-3337719/v1.
(gatsi2014prohibitinmediatedlifespanand pages 1-2): Roxani Gatsi, Bettina Schulze, María Jesús Rodríguez-Palero, Blanca Hernando-Rodríguez, Ralf Baumeister, and Marta Artal-Sanz. Prohibitin-mediated lifespan and mitochondrial stress implicate sgk-1, insulin/igf and mtorc2 in c. elegans. PLoS ONE, 9:e107671, Sep 2014. URL: https://doi.org/10.1371/journal.pone.0107671, doi:10.1371/journal.pone.0107671. This article has 55 citations and is from a peer-reviewed journal.
(gatsi2014prohibitinmediatedlifespanand pages 2-3): Roxani Gatsi, Bettina Schulze, María Jesús Rodríguez-Palero, Blanca Hernando-Rodríguez, Ralf Baumeister, and Marta Artal-Sanz. Prohibitin-mediated lifespan and mitochondrial stress implicate sgk-1, insulin/igf and mtorc2 in c. elegans. PLoS ONE, 9:e107671, Sep 2014. URL: https://doi.org/10.1371/journal.pone.0107671, doi:10.1371/journal.pone.0107671. This article has 55 citations and is from a peer-reviewed journal.
(wei2017prohibitin2is pages 1-3): Yongjie Wei, Wei-Chung Chiang, Rhea Sumpter, Prashant Mishra, and Beth Levine. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell, 168:224-238.e10, Jan 2017. URL: https://doi.org/10.1016/j.cell.2016.11.042, doi:10.1016/j.cell.2016.11.042. This article has 932 citations and is from a highest quality peer-reviewed journal.
(lourenco2021themitochondrialprohibitin pages 12-13): Artur B. Lourenço and Marta Artal-Sanz. The mitochondrial prohibitin (phb) complex in c. elegans metabolism and ageing regulation. Metabolites, 11:636, Sep 2021. URL: https://doi.org/10.3390/metabo11090636, doi:10.3390/metabo11090636. This article has 16 citations.
(wei2017prohibitin2is pages 12-13): Yongjie Wei, Wei-Chung Chiang, Rhea Sumpter, Prashant Mishra, and Beth Levine. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell, 168:224-238.e10, Jan 2017. URL: https://doi.org/10.1016/j.cell.2016.11.042, doi:10.1016/j.cell.2016.11.042. This article has 932 citations and is from a highest quality peer-reviewed journal.
(wei2017prohibitin2is pages 4-5): Yongjie Wei, Wei-Chung Chiang, Rhea Sumpter, Prashant Mishra, and Beth Levine. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell, 168:224-238.e10, Jan 2017. URL: https://doi.org/10.1016/j.cell.2016.11.042, doi:10.1016/j.cell.2016.11.042. This article has 932 citations and is from a highest quality peer-reviewed journal.
(lahiri2017phb2prohibitin2an pages 1-2): Vikramjit Lahiri and Daniel J Klionsky. Phb2/prohibitin 2: an inner membrane mitophagy receptor. Cell Research, 27:311-312, Feb 2017. URL: https://doi.org/10.1038/cr.2017.23, doi:10.1038/cr.2017.23. This article has 62 citations and is from a domain leading peer-reviewed journal.
(qi2023essentialproteinphb2 pages 5-6): Amanda Qi, Lillie Lamont, Evelyn Liu, Sarina D. Murray, Xiangbing Meng, and Shujie Yang. Essential protein phb2 and its regulatory mechanisms in cancer. Cells, 12:1211, Apr 2023. URL: https://doi.org/10.3390/cells12081211, doi:10.3390/cells12081211. This article has 34 citations.
(belser2021roleofprohibitins pages 1-2): Misa Belser and David W. Walker. Role of prohibitins in aging and therapeutic potential against age-related diseases. Frontiers in Genetics, Oct 2021. URL: https://doi.org/10.3389/fgene.2021.714228, doi:10.3389/fgene.2021.714228. This article has 27 citations and is from a peer-reviewed journal.
(gatsi2014prohibitinmediatedlifespanand pages 3-4): Roxani Gatsi, Bettina Schulze, María Jesús Rodríguez-Palero, Blanca Hernando-Rodríguez, Ralf Baumeister, and Marta Artal-Sanz. Prohibitin-mediated lifespan and mitochondrial stress implicate sgk-1, insulin/igf and mtorc2 in c. elegans. PLoS ONE, 9:e107671, Sep 2014. URL: https://doi.org/10.1371/journal.pone.0107671, doi:10.1371/journal.pone.0107671. This article has 55 citations and is from a peer-reviewed journal.
(gatsi2014prohibitinmediatedlifespanand pages 6-8): Roxani Gatsi, Bettina Schulze, María Jesús Rodríguez-Palero, Blanca Hernando-Rodríguez, Ralf Baumeister, and Marta Artal-Sanz. Prohibitin-mediated lifespan and mitochondrial stress implicate sgk-1, insulin/igf and mtorc2 in c. elegans. PLoS ONE, 9:e107671, Sep 2014. URL: https://doi.org/10.1371/journal.pone.0107671, doi:10.1371/journal.pone.0107671. This article has 55 citations and is from a peer-reviewed journal.
(lourenco2021themitochondrialprohibitin pages 7-8): Artur B. Lourenço and Marta Artal-Sanz. The mitochondrial prohibitin (phb) complex in c. elegans metabolism and ageing regulation. Metabolites, 11:636, Sep 2021. URL: https://doi.org/10.3390/metabo11090636, doi:10.3390/metabo11090636. This article has 16 citations.