The BCL2L13 gene produces a protein that regulates cell fate, balancing cell survival and programmed cell death. Although a relatively recent focus of study, its functions are fundamental for maintaining cellular health. Because it can initiate the removal of damaged cell components or trigger cell death, BCL2L13 is central to the quality control systems that keep tissues functioning correctly. Understanding this dual role is important for researchers investigating aging, metabolic diseases, and cancer development.
Defining BCL2L13: A Member of the Bcl-2 Protein Family
BCL2L13 belongs to the B-cell lymphoma 2 (Bcl-2) protein family, which controls the intrinsic pathway of programmed cell death. The gene is located on human chromosome 22 at band 22q11.21 and is sometimes called Bcl-rambo. The protein contains conserved Bcl-2 homology (BH) motifs, structural domains that dictate how family members interact with other cellular proteins.
The BCL2L13 protein is primarily situated in the mitochondrial outer membrane. This location allows it to monitor the health and function of the cell’s mitochondria. Anchoring to the membrane is facilitated by a transmembrane (TM) motif found at its C-terminus.
The Bcl-2 family is traditionally divided into anti-apoptotic and pro-apoptotic members. BCL2L13 is complex because it possesses structural features enabling it to participate in both cell fate mechanisms. Its role depends entirely on the specific conditions within the cell.
Primary Role: BCL2L13 and the Mechanism of Mitophagy
The most distinct function of the BCL2L13 protein is its role as a receptor for mitophagy, the selective degradation and recycling of damaged mitochondria. Mitophagy is a specialized form of autophagy, where components are enclosed in an autophagosome and delivered to the lysosome for breakdown. This quality control mechanism prevents the accumulation of dysfunctional mitochondria that generate harmful reactive oxygen species.
BCL2L13 acts as a direct mitophagy receptor, distinguishing it from other Bcl-2 family members. This function makes BCL2L13 the functional mammalian equivalent of the Atg32 protein found in yeast. Embedded in the outer mitochondrial membrane, BCL2L13 initiates the removal process when the organelle is damaged.
The protein contains an LC3-interacting region (LIR) motif, which allows it to directly bind to proteins of the LC3/GABARAP family. These proteins are anchored to the growing autophagosome membrane. The binding interaction physically tethers the damaged mitochondrion to the engulfing vesicle, ensuring the compromised organelle is targeted for destruction.
BCL2L13-mediated mitophagy is a ubiquitin-independent pathway, meaning it does not rely on ubiquitin tags on the mitochondrial surface, unlike the Parkin/PINK1 pathway. BCL2L13 activation is regulated by kinases such as AMP-activated protein kinase (AMPK) and TANK-binding kinase 1 (TBK1) upon mitochondrial stress. The protein also cooperates with the ULK1 kinase complex, which is necessary for autophagosome formation.
BCL2L13 also promotes mitochondrial fragmentation before the engulfment process, breaking the organelle into smaller pieces for removal. This fission process is facilitated by the protein’s ability to trigger the phosphorylation of DNM1L, a protein that drives mitochondrial division. The simultaneous promotion of fragmentation and direct recruitment of the autophagosome shows BCL2L13 coordinates mitochondrial turnover.
Secondary Role: Regulating Programmed Cell Death (Apoptosis)
Separate from organelle clearance, BCL2L13 also functions in the intrinsic pathway of programmed cell death, or apoptosis. This was the first function discovered for the protein, classifying it as a pro-apoptotic member of the Bcl-2 family. When the cell receives a strong death signal, BCL2L13 contributes to the cascade that leads to the cell’s systematic dismantling.
This signaling involves BCL2L13 interacting with proteins embedded in the mitochondrial outer membrane, such as the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC). These interactions induce the opening of the mitochondrial permeability transition pore (MPTP). Opening this pore causes the mitochondrial outer membrane to become permeable (MOMP), destabilizing the organelle.
Once the mitochondrial membrane is compromised, pro-death factors like cytochrome c are released into the cytoplasm. Cytochrome c then activates caspases, which are the final executioners of the apoptotic process. BCL2L13’s ability to induce this cascade is a mechanism for eliminating severely damaged or genetically unstable cells.
BCL2L13’s apoptotic role is complex and context-dependent, sometimes displaying anti-apoptotic activity. In certain brain tumor cells, BCL2L13 inhibits cell death by binding to and blocking ceramide synthases. Therefore, whether BCL2L13 favors mitophagy or apoptosis depends on the cell type, interacting partners, and specific molecular signals present.
Clinical Significance and Disease Association
The dual functions of BCL2L13 in mitochondrial quality control and cell death signaling mean its dysregulation is a factor in several major human diseases. Severe consequences occur when the balance between clearing damaged mitochondria and triggering cell death is lost.
Failure of BCL2L13-mediated mitophagy is implicated in neurodegenerative disorders. The inability to efficiently remove damaged mitochondria leads to their buildup in highly metabolic cells like neurons. This accumulation contributes to the cellular stress and dysfunction observed in conditions such as Parkinson’s disease and Alzheimer’s disease.
The role of BCL2L13 in cancer is highly variable and depends on the tumor type. In some cancers, such as glioblastoma, the protein is upregulated, promoting cell survival by enhancing protective mitophagy. Tumor cells use BCL2L13 to clear damaged mitochondria, allowing malignant cells to maintain metabolic function and resist therapy.
Conversely, a lower expression of BCL2L13 is sometimes observed in other malignancies, such as certain types of breast cancer or lung adenocarcinoma. This inconsistency suggests the protein’s overall effect is highly dependent on the molecular environment of the cancer cell. The complex activity of BCL2L13 makes it a subject of intense research for potential therapeutic targeting.