ABSTRACT
Mitochondrial dysfunction is a hallmark of metabolic diseases, including diabetes, yet the downstream consequences of mitochondrial damage in metabolic tissues are often unclear. Here, we report that mitochondrial dysfunction engages a retrograde signaling program that impairs cellular identity and maturity across many metabolic tissues. Impairments in the mitochondrial quality control machinery, which we observe in pancreatic β cells of humans with diabetes, cause reductions of β cell mass, surprisingly due to β cell dedifferentiation, rather than apoptosis. Utilizing transcriptomic profiling, lineage tracing, and assessments of chromatin accessibility, we find that targeted defects anywhere in the mitochondrial quality control pathway (genome integrity, dynamics, or turnover) activate the mitochondrial integrated stress response and promote cellular immaturity in β cells, hepatocytes, and brown adipocytes. Intriguingly, pharmacologic blockade of mitochondrial retrograde signals restores β cell mass and identity to ameliorate hyperglycemia following mitochondrial damage. Thus, we observe that a shared mitochondrial retrograde response controls cellular identity across metabolic tissues, which could be a promising target to treat or prevent metabolic diseases.
Competing Interest Statement
The authors have declared no competing interest.
