Mitophagy protects β cells from inflammatory damage in diabetes. JCI Insight 2020 Dec 17;5(24)
Date
11/25/2020Pubmed ID
33232298Pubmed Central ID
PMC7819751DOI
10.1172/jci.insight.141138Scopus ID
2-s2.0-85097820706 (requires institutional sign-in at Scopus site) 59 CitationsAbstract
Inflammatory damage contributes to β cell failure in type 1 and 2 diabetes (T1D and T2D, respectively). Mitochondria are damaged by inflammatory signaling in β cells, resulting in impaired bioenergetics and initiation of proapoptotic 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 β cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic proinflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β 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 β cell apoptosis. Thus, mitophagy promotes β cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent β cell failure in diabetes and may be beneficial in other inflammatory conditions.
Author List
Sidarala V, Pearson GL, Parekh VS, Thompson B, Christen L, Gingerich MA, Zhu J, Stromer T, Ren J, Reck EC, Chai B, Corbett JA, Mandrup-Poulsen T, Satin LS, Soleimanpour SAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Survival
Diabetes Complications
Diabetes Mellitus
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Disease Models, Animal
Female
Humans
Inflammation
Insulin-Secreting Cells
Lectins, C-Type
Male
Mice
Mice, Inbred C57BL
Mitochondria
Monosaccharide Transport Proteins
Oxidative Stress
Primary Cell Culture
Protective Agents
Signal Transduction
