ATAD3B is a mitochondrial membrane protein that acts as a stress-responsive mitophagy receptor for selective clearance of damaged mitochondrial DNA PMID:33665835. Under basal conditions it hetero-oligomerizes with ATAD3A, which targets the ATAD3B C-terminus to the intermembrane space and negatively regulates ATAD3A's interaction with matrix nucleoid complexes, positioning ATAD3B as a dominant-negative modulator of ATAD3A whose loss perturbs mitochondrial morphology [PMID:33665835, PMID:22664726]. Oxidative stress-induced mtDNA damage or depletion disrupts the ATAD3B-ATAD3A hetero-oligomer, exposing the ATAD3B C-terminus at the outer mitochondrial membrane where its LIR motif directly binds LC3 to initiate mitophagy independently of PINK1 PMID:33665835. This pathway is functionally consequential: ATAD3B re-expression promotes clearance of pathogenic m.3243A>G mutant mtDNA PMID:33665835. ATAD3B is encoded as two mitochondrially localized isoforms that are early transcriptional targets of c-Myc and are required for normal cell division, with knockdown producing polynuclear cells, reduced proliferation, and apoptosis PMID:16909202. At mitochondria-associated membranes, the ER protein SEC62 directly binds ATAD3B and suppresses its expression, dampening mitophagy and amplifying mitochondrial ROS and inflammation PMID:42001994.
| Year | Confidence | Finding | PMIDs | Journal |
|---|---|---|---|---|
| 2021 | High | ATAD3B contains a LIR (LC3-interacting region) motif that directly binds LC3 and functions as a mitophagy receptor, promoting oxidative stress-induced mitophagy in a PINK1-independent manner to clear damaged mtDNA. | PMID:33665835 | The EMBO journal |
| 2021 | High | Under normal conditions, ATAD3B hetero-oligomerizes with ATAD3A, which promotes targeting of the ATAD3B C-terminal region to the mitochondrial intermembrane space. Oxidative stress-induced mtDNA damage or depletion reduces this ATAD3B-ATAD3A hetero-oligomerization, leading to exposure of the ATAD3B C-terminus at the mitochondrial outer membrane and subsequent LC3 recruitment for mitophagy initiation. | PMID:33665835 | The EMBO journal |
| 2012 | Medium | ATAD3B associates with ATAD3A (hetero-oligomerization), negatively regulates the interaction of ATAD3A with matrix nucleoid complexes, and contributes to a mitochondrial fragmentation phenotype. ATAD3B thus functions as a dominant negative regulator of ATAD3A. | PMID:22664726 | Mitochondrion |
| 2006 | Medium | The ATAD3B gene encodes two distinct protein isoforms (AAA-TOB3s and AAA-TOB3l) generated from distinct transcription initiation sites, both localized to mitochondria. Both isoforms are early transcriptional targets of c-Myc. Knockdown of both isoforms results in polynuclear cells, decreased proliferation, dysfunctional cell division, and increased apoptosis, indicating a required role in cell division. | PMID:16909202 | Cellular and molecular life sciences : CMLS |
| 2026 | Medium | SEC62, an ER transmembrane protein at mitochondria-associated membranes (MAMs), directly interacts with ATAD3B and suppresses ATAD3B expression, leading to defective mitophagy, increased mitochondrial ROS, and amplified inflammatory responses in MASH. | PMID:42001994 | Metabolism: clinical and experimental |
| 2021 | Medium | ATAD3B re-expression in cells with m.3243A>G mutated mtDNA promotes clearance of the mutant mtDNA, demonstrating a functional role of ATAD3B-mediated mitophagy in eliminating pathogenic mtDNA variants. | PMID:33665835 | The EMBO journal |