Translational Medicine Program, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
Department of Physiology, University of Toronto, Toronto, ON, M5S 1A1, Canada.
Cell Mol Life Sci. 2023 Jun 20;80(7):183. doi: 10.1007/s00018-023-04827-3.
Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.
过氧化物酶体对于线粒体的健康至关重要，因为过氧化物酶体的缺失会导致线粒体发生改变。然而，目前尚不清楚线粒体的变化是为了维持细胞功能的一种功能，还是对过氧化物酶体缺失引起的细胞损伤的一种反应。为了解决这个问题，我们构建了条件性肝细胞特异性 Pex16 缺失（Pex16 KO）小鼠，这些小鼠会发生过氧化物酶体缺失，并接受低蛋白饮食以诱导代谢应激。肝细胞中 PEX16 的缺失导致小线粒体的生物发生增加和自噬通量减少，但呼吸和 ATP 能力得以保留。低蛋白喂养引起的代谢应激导致 Pex16 KO 小鼠的线粒体功能障碍和生物发生受损。PPARα 的激活部分纠正了这些线粒体紊乱，尽管过氧化物酶体缺失。本研究的结果表明，肝细胞中过氧化物酶体的缺失会导致协调一致的努力来维持线粒体功能，包括增加线粒体生物发生、改变形态和修饰自噬活性。我们的研究强调了过氧化物酶体和线粒体在调节肝脏对营养应激的代谢反应中的关系。
