Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield…

• AD
  American Diabetes Association

  Awards: DK020572, 19-PDF-063
• UD
  U.S. Department of Veterans Affairs

  Awards: BX004444, P30 DK020572, U24DK098085, I01 BX004444
• UO
  University of Alberta

  Award: Pro00013094
• NN
  Novo Nordisk
• NI
  National Institutes of Health

  Awards: R01 DK108921, U24DK098085, R01 DK142799, R01 DK135032, U01 DK127747, R01 DK136671, DK46409, DK135032, P30 DK020572, R01 DK46409, R01 DK135268, SCR _014387, DK020572, DK127270, R01 DK127270, DK48280, K01 DK133533, R01 DK48280
• NI
  National Institute of Diabetes and Digestive and Kidney Diseases

  Awards: R01 DK108921, DK020572, R01 DK135268, SCR _014387, U01 DK127747, U24DK098085, R01 DK135032, U2CDK135066, R01 DK48280, P30 DK020572, DK108921, K01 DK133533, DK46409, DK48280