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

Myeloid Cell Leukemia-1 (MCL-1) is an anti-apoptotic protein that is crucial for early neurodevelopment. Loss of MCL-1 results in embryonic lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the BCL-2 family. Here, we find a non-apoptotic role for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation (FAO), and neural progenitor identity in human neural stem cells (hNSCs). Pharmacological inhibition of MCL-1 with S63845 disrupts mitochondrial ultrastructure, leading to swollen mitochondria with disorganized cristae and destabilization of the OPA1-MICOS machinery that governs inner membrane architecture. These structural defects are accompanied by impaired lipid droplet accumulation and altered expression of beta-oxidation enzymes, revealing a tight link between cristae architecture and metabolic competence. Functionally, in the absence of caspase-mediated cell death, MCL-1 inhibition selectively depletes intermediate progenitor cells and alters neuronal differentiation without affecting proliferation, indicating a direct role in lineage progression. Together, our findings identify MCL-1 as a modulator of cristae organization, linking lipid metabolism to neural progenitor fate. This work establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights the non-canonical MCL-1 functions as critical regulators of human brain development