Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]
Fan Zheng,
Zanlin Yu,
Junming Zhuang,
Lingraj Vannur,
William Nickols,
YongQiang Wang,
Liying Li,
Sho Joseph Ozaki Tan,
Seungmin Yoo,
Yifan Cheng,
Chuankai Zhou.
Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.
Keywords: aging; metabolism; mitochondria; mitoribosome; translation activity