Mitophagy protects beta cells from inflammatory damage in diabetes

Abstract

Inflammatory damage contributes to {beta}-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in {beta}-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent {beta}-cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient {beta}-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased {beta}-cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human {beta}-cell apoptosis. Thus, mitophagy promotes {beta}-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent {beta}-cell failure in diabetes and may be beneficial in other inflammatory conditions.