Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

Mitochondrial dysfunction is a hallmark of metabolic diseases, including diabetes, yet the consequences of mitochondrial damage in metabolic tissues are often unclear. Here, we report that mitochondrial dysfunction engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity across many metabolic tissues. Surprisingly, we demonstrate that impairments in the mitochondrial quality control machinery, which we observe in pancreatic β cells of humans with diabetes, cause reductions of β cell mass due to 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 (e.g., 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 signaling in vivo 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 and may be a promising target to treat or prevent metabolic diseases.