Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY, USA.
Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, USA.
FEBS Lett. 2018 Mar;592(5):759-775. doi: 10.1002/1873-3468.12894. Epub 2017 Nov 14.
In addition to its central role in energy metabolism, the mitochondrion has many other functions essential for cell survival. When stressed, the multifunctional mitochondria are expected to engender multifaceted cell stress with complex physiological consequences. Potential extra-mitochondrial proteostatic burdens imposed by inefficient protein import have been largely overlooked. Accumulating evidence suggests that a diverse range of pathogenic mitochondrial stressors, which do not directly target the core protein import machinery, can reduce cell fitness by disrupting the proteostatic network in the cytosol. The resulting stress, named mitochondrial precursor overaccumulation stress (mPOS), is characterized by the toxic accumulation of unimported mitochondrial proteins in the cytosol. Here, we review our current understanding of how mitochondrial dysfunction can impact the cytosolic proteome and proteostatic signaling. We also discuss the intriguing possibility that the mPOS model may help untangle the cause-effect relationship between mitochondrial dysfunction and cytosolic protein aggregation, which are probably the two most prominent molecular hallmarks of neurodegenerative disease.
除了在能量代谢中的核心作用外，线粒体还有许多其他对细胞生存至关重要的功能。当受到压力时，多功能线粒体预计会产生多方面的细胞应激，产生复杂的生理后果。人们在很大程度上忽视了低效蛋白质导入可能带来的潜在额外的线粒体蛋白质稳态负担。越来越多的证据表明，一系列不同的致病性线粒体应激源，这些应激源并不直接针对核心蛋白质导入机制，通过破坏细胞质中的蛋白质稳态网络，可以降低细胞适应性。由此产生的应激被称为线粒体前体积累过度应激（mPOS），其特征是未导入的线粒体蛋白质在细胞质中有毒积累。在这里，我们回顾了我们目前对线粒体功能障碍如何影响细胞质蛋白质组和蛋白质稳态信号的理解。我们还讨论了一个有趣的可能性，即 mPOS 模型可能有助于理清线粒体功能障碍和细胞质蛋白质聚集之间的因果关系，这可能是神经退行性疾病的两个最突出的分子特征。
