Emily Walker, PhD

Research Assistant Professor, Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan

“Mitochondrial retrograde signaling governs the identity and maturity of metabolic tissues”

Abstract

Mitochondrial damage is a hallmark of metabolic diseases, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). Defects in mitochondrial structure, gene expression, and energetics previously observed in T2D could arise due to impairments in mitochondrial quality control. We hypothesized that models of impaired mitophagy, mitochondrial genome integrity, or mitochondrial fusion in isolation would allow us to parse the contribution of each mitochondrial quality control defect to β-cell failure in T2D. In pancreatic β-cells of donors with T2D we observed impairments in mitochondrial genome integrity, mitochondrial RNA expression, and mitophagy. Furthermore, comparing the top 500 up- and down-regulated genes across our models of impaired mitochondrial quality control revealed a common activation of the mitochondrial integrated stress response (mtISR), a retrograde (mitonuclear) signaling program. Loss of cell identity and maturity was due to dedifferentiation, confirmed by genetic lineage tracing, rather than apoptosis. Importantly, pharmacologic blockade of mitochondrial retrograde signaling in vivo restored β-cell mass and identity following mitochondrial damage. Targeting mitochondrial retrograde signaling in metabolic tissues may be promising in the treatment or prevention of diabetes and other metabolic disorders.