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bioRxiv · 10.64898/2025.12.12.694056

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

Hanna, M. R.·Yarbrough, M.·Gil, M.·Costanzo, J.·Gama, V.
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Abstract

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.

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Hanna, M. R., Yarbrough, M., Gil, M., Costanzo, J., Gama, V.. 2025-12-14. Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool. https://doi.org/10.64898/2025.12.12.694056

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