Mitophagy is an essential quality control mechanism to ensure a healthy mitochondrial pool is available to fuel tissues of high energy demand. PPTC7, a mitochondrial phosphatase, has recently emerged as a potent negative regulator of BNIP3- and NIX-mediated mitophagy, as Pptc7 knockout results in the upregulation of these mitophagy receptors and subsequent unchecked and excessive mitophagy in cultured cells. As the physiological responses to excessive mitophagy are largely unknown, the goal of our study was to investigate how knockout of the negative mitophagic regulator Pptc7 affects murine physiology from the organellar to the organismal level. Given that PPTC7 protein expression is highest in metabolically active tissues, such as the heart and skeletal muscle, we hypothesized these tissues would exhibit elevated BNIP3 protein expression and mitophagy, hindering their ability to maintain a sufficient mitochondrial population to respire effectively. Using multiple mouse models, enzymatic assays, immunoblotting, and high-resolution respirometry, we discovered surprisingly variable tissue-specific adaptations to the loss of PPTC7. In skeletal muscle, all tested Pptc7 knockout muscles showed increased BNIP3 protein levels concomitant to lower mitochondrial content. Despite the development of selective muscle atrophy, isolated mitochondria from Pptc7 knockout skeletal muscle maintained oxygen consumption rates indistinguishable from control organelles. These data suggest that, in skeletal muscle, loss of PPTC7 hyperactivates BNIP3-mediated mitophagy, leading to fewer mitochondria to trigger skeletal muscle atrophy. Consistently, heart tissue from Pptc7 knockout animals also showed signs of elevated mitophagy, harboring significant elevation in BNIP3 protein expression. However, unlike skeletal muscle, Pptc7 knockout cardiac tissue displayed similar mitochondrial content relative to control tissues, but harbored mitochondria that, when isolated, had significantly compromised oxygen consumption rates. These data suggest that in cardiac muscle, loss of PPTC7 triggers mitochondrial-intrinsic dysfunction, which likely contributes to the development of dilated cardiomyopathy and sudden, premature death in cardiomyocyte-specific Pptc7 knockout mice. Together, these data demonstrate that metabolically active tissues such as striated muscles have distinct responses to the loss of PPTC7, with some tissues decreasing mitochondrial content but maintaining organellar function, and other tissues maintaining mitochondrial content but manifesting compromised respiration. As we recently identified PPTC7 as a dual-localized regulator of mitophagy as well as a matrix-localized protein phosphatase, these differential functions of PPTC7 are likely to contribute to these tissue-specific effects. Overall, these data reveal surprisingly distinct physiological responses to loss of PPTC7, underscoring the importance of proper regulation of various mitochondrial functions across metabolically active tissues such as striated muscle. This work was partially supported by the Longer Life Foundation (2023-2024). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Lochetto et al. (Fri,) studied this question.