Mitophagy protects beta cells from inflammatory damage in diabetes

Sidarala, V.; Pearson, G. L.; Parekh, V. S.; Thompson, B.; Christen, L.; Gingerich, M. A.; Zhu, J.; Stromer, T.; Ren, J.; Reck, E.; Chai, B.; Corbett, J. A.; Mandrup-Poulsen, T.; Satin, L. S.; Soleimanpour, S. A.

doi:10.1101/2020.06.07.138917

bioRxiv · 10.1101/2020.06.07.138917

Mitophagy protects beta cells from inflammatory damage in diabetes

Sidarala, V.·Pearson, G. L.·Parekh, V. S.·Thompson, B.·Christen, L.·Gingerich, M. A.·Zhu, J.·Stromer, T.·Ren, J.·Reck, E.·Chai, B.·Corbett, J. A.·Mandrup-Poulsen, T.·Satin, L. S.·Soleimanpour, S. A.

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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.

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Sidarala, V., Pearson, G. L., Parekh, V. S., Thompson, B., Christen, L., Gingerich, M. A., Zhu, J., Stromer, T., Ren, J., Reck, E., Chai, B., Corbett, J. A., Mandrup-Poulsen, T., Satin, L. S., Soleimanpour, S. A.. 2020-06-09. Mitophagy protects beta cells from inflammatory damage in diabetes. https://doi.org/10.1101/2020.06.07.138917

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