Hanna, M. R. | Search bioRxiv

bioRxiv2025

Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool

MCL-1 is a canonical anti-apoptotic protein crucial for early neurodevelopment, and its loss causes embryonic-lethal defects that other BCL-2 family proteins cannot rescue. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and uncover non-apoptotic roles in sustaining mitochondrial cristae integrity, fatty acid oxidation, and progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, destabilizing the OPA1-MICOS machinery. These structural defects are accompanied by ACSL1 displacement from the mitochondria, impaired fatty acid oxidation, lipid droplet accumulation, and reduced oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner membrane and retaining ACSL1 at the outer membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS, and ACSL1 as a critical coordinator of cristae organization, lipid metabolism, and neural progenitor fate, establishing mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlighting non-canonical MCL-1 functions as regulators of brain development.

cell biology↗

bioRxiv2024

MCL-1 regulates cellular transitions during oligodendrocyte development

Oligodendrocytes are the myelinating cells of the central nervous system. Regulation of the early stages of oligodendrocyte development is critical to the function of the cell. Specifically, myelin sheath formation is an energetically demanding event that requires precision, as alterations may lead to dysmyelination. Recent work has established that fatty acid {beta}-oxidation is required for the function of oligodendrocytes. We have shown that MCL-1, a well-characterized anti-apoptotic protein, is required for the development of oligodendrocytes in vivo. Further, it was recently uncovered that MCL-1 regulates long- chain fatty acid {beta}-oxidation through its interaction with acyl-CoA synthetase long-chain family member 1 (ACSL1), an enzyme responsible for the conversion of long-chain fatty acids into acyl-CoA. Here, we introduce an in vitro system to isolate human stem cell- derived oligodendrocyte progenitor cells and investigate the involvement of MCL-1 during human oligodendrocyte development. Using this system, we pharmacologically inhibited MCL-1 in oligodendrocyte progenitor cells (OPCs) to elucidate the non-apoptotic function of the protein at this developmental stage. Additionally, we used a motor neuron co-culture system to investigate the downstream effects that MCL-1 inhibition has at later developmental stages when oligodendrocytes begin to contact axons and generate myelin basic protein. We demonstrate that the mitochondrial network changes in human oligodendrocyte development resemble those reported in vivo. Our findings point to MCL-1 as a critical factor essential at the OPC stage for proper oligodendrocyte morphogenesis.

cell biology↗