Mitochondrial dysfunction by TFAM depletion disrupts self-renewal and lineage differentiation of human PSCs by affecting cell proliferation and YAP response

Genetic mitochondrial dysfunction is frequently associated with various embryonic developmental defects. However, how mitochondria contribute to early development and cell fate determination is poorly studied, especially in humans. Using human pluripotent stem cells (hPSCs), we established a Dox-induced knockout model with mitochondrial dysfunction and evaluated the effect of mitochondrial dysfunction on human pluripotency maintenance and lineage differentiation. The nucleus-encoded gene TFAM (transcription factor A, mitochondrial), essential for mitochondrial gene transcription and mitochondrial DNA replication, is targeted to construct the mitochondrial dysfunction model. The hPSCs with TFAM depletion exhibit the decrease of mtDNA level and oxidative respiration efficiency, representing a typical mitochondrial dysfunction phenotype. Mitochondrial dysfunction leads to impaired self-renewal in hPSCs due to proliferation arrest. Although the mitochondrial dysfunction does not affect pluripotent gene expression, it results in a severe defect in lineage differentiation. Further study in mesoderm differentiation reveals that mitochondrial dysfunction causes proliferation disability and YAP nuclear translocalization and thus together blocks mesoderm lineage differentiation. These findings provide new insights into understanding the mitochondrial function in human pluripotency maintenance and mesoderm differentiation.

Automated summary

Mitochondrial dysfunction is associated with embryonic developmental defects and affects human pluripotency maintenance and lineage differentiation. In this study, a Dox-induced knockout model with mitochondrial dysfunction was established using hPSCs. It was found that mitochondrial dysfunction leads to impaired self-renewal in hPSCs and severe defects in lineage differentiation.