MTLN (mitoregulin; MOXI / MPM / LEMP / SMIM37) review notes

UniProt Q8NCU8 (MTLN_HUMAN), 56 aa, encoded by LINC00116 (mouse 1500011K16Rik).
Single predicted TM helix (res 10-27); UniProt topology (by similarity to mouse Q8BT35):
N-terminus matrix, C-terminal basic tail in the intermembrane space. Initiator Met removed
(top-down MS of human mitochondrial membrane proteins, PMID:23305238 per UniProt).
Family: InterPro IPR038778, PANTHER PTHR37154, Pfam PF22002 -- vertebrate-restricted.

Session 2026-09-30 (claude-code)

Discovery (2018-2020): four groups, four names

• Stein et al. 2018 (Boudreau lab; "mitoregulin"): PMID:29949756
• Cardiolipin: PMID:29949756 and PMID:29949756 -- assay on mouse heart lysate (mouse Mtln).
• Supercomplexes (mouse KO): PMID:29949756; PMID:29949756
• BN-PAGE: PMID:29949756
• Human cell data: HeLa Dox-On overexpression increases membrane potential, respiration, Ca2+
  retention; overexpression did not change SC levels (PMID:29949756). So the supercomplex evidence is loss-of-function in mouse; the human IDA
  for respirasome assembly probably reflects the curator's reading of the whole paper.
• Authors frame FAO defect as downstream: PMID:29949756
• Makarewich et al. 2018 (Olson lab; "MOXI"), mouse: PMID:29949755; MTP
  levels unaffected: PMID:29949755. KO mitochondria oxidise fatty acids less, TG overexpression more.
• Chugunova et al. 2019 (Sergiev/Dontsova), mouse cell lines: complex I activity reduced in KO but
  PMID:30796188 Partner is CYB5R3:
  PMID:30796188
• Lin et al. 2019 ("MPM"), mouse C2C12/KO: myogenic differentiation phenotype, attributed to
  respiration: PMID:31296841 -- source of the mouse IMP for striated muscle cell differentiation and
  cellular respiration that were ISS-transferred to human.
• Wang et al. 2020 ("LEMP"), mouse + zebrafish myogenesis: PMID:32393776.
• Friesen et al. 2020 (human hPSC-adipocytes + mouse KO): PMID:32243843; co-IP of HADHB and ATP5B
  PMID:32243843.
  Source of all human IPI/IMP/IDA rows other than respirasome assembly.
  Mechanism is regulatory: PMID:32243843

Later work (2023-2026)

• Localisation dispute. Zhang et al. 2023 (human cells; split-GFP topology, protease protection):
  PMID:37664623 Interactors CPT1B,
  CYB5B, CYB5R3, ACSL1, VDAC3; KO accumulates VLCFA/DHA. The Boudreau lab continues to model
  Mtln in the IMM/cristae (PMID:41555203, PMID:39811642). Not resolved; IMM annotations kept, OMM
  raised as a question rather than a NEW annotation.
• Self-association: PMID:39811642 (~66 kDa complex, synthetic
  protein; human and mouse).
• Membrane role: PMID:41555203 Synthetic human Mtln alters
  IMM-like lipid monolayers; KO cristae defects, CL damage/MLCL increase.
• Averina 2023 (mouse KO): obesity on HFD, elevated serum TG (PMID:36174793, abstract only);
  muscle CL decrease/MLCL increase, MtCK octamer dissociation (PMID:37108753).
• Li 2023 Kidney Int (PMID:36804379): MOXI nuclear translocation in fibrotic kidney -- abstract
  only, single report, not used for GO.

Synthesis

The most direct molecular observation is lipid (cardiolipin) binding and membrane modulation, plus
physical association with several IMM/OMM enzyme complexes (MTP, ATP synthase, CYB5R3, CPT1B).
There is no catalytic activity. Respiratory supercomplex (respirasome) assembly/stability and
enhanced FAO are the best-supported processes; both plausibly follow from a membrane-organising,
CL-binding role. Downstream phenotypes (TG accumulation, obesity on HFD, myogenic
differentiation defects, exercise capacity) are consequences of reduced oxidative capacity.

Decisions:
- protein binding IPIs (HADHB, ATP5F1B): REMOVE (uninformative; interactions real but no specific MF
can be inferred -- MTLN not required for MTP formation/stability).
- fatty acid beta-oxidation IMP: MODIFY -> positive regulation of fatty acid beta-oxidation
(MTLN does not catalyse a step; enhances rate).
- triglyceride homeostasis IMP, striated muscle cell differentiation, lipid metabolic process,
cellular respiration: KEEP_AS_NON_CORE (indirect/broad).
- respirasome assembly, IMM, mitochondrion, positive regulation of FAO: ACCEPT.
- NEW: cardiolipin binding (GO:1901612), ISS from mouse data in PMID:29949756, supported for the
human peptide by PMID:41555203 (synthetic human Mtln in lipid monolayers).
- Considered but not proposed: GO:0010918 positive regulation of mitochondrial membrane potential
(appears as IBA in UniProt DR lines but not in this GOA download; phenotype-level readout of
overexpression); GO:0005741 mitochondrial outer membrane (contested); identical protein binding
(self-association) -- uninformative.