Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy

Niemi, N. M.; Serrano, L. R.; Muehlbauer, L. K.; Balnis, C.; Kozul, K.-L.; Rashan, E. H.; Shishkova, E.; Schueler, K. L.; Keller, M. P.; Attie, A. D.; Pagan, J.; Coon, J. J.; Pagliarini, D. J.

doi:10.1101/2023.02.28.530351

bioRxiv · 10.1101/2023.02.28.530351

Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy

Niemi, N. M.·Serrano, L. R.·Muehlbauer, L. K.·Balnis, C.·Kozul, K.-L.·Rashan, E. H.·Shishkova, E.·Schueler, K. L.·Keller, M. P.·Attie, A. D.·Pagan, J.·Coon, J. J.·Pagliarini, D. J.

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Abstract

Pptc7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass concomitant with elevation of the mitophagy receptors Bnip3 and Nix. Consistently, Pptc7-/- mouse embryonic fibroblasts (MEFs) exhibit a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs-- including multiple sites on Bnip3 and Nix. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that Pptc7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for Pptc7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.

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Niemi, N. M., Serrano, L. R., Muehlbauer, L. K., Balnis, C., Kozul, K.-L., Rashan, E. H., Shishkova, E., Schueler, K. L., Keller, M. P., Attie, A. D., Pagan, J., Coon, J. J., Pagliarini, D. J.. 2023-03-01. Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy. https://doi.org/10.1101/2023.02.28.530351

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