The mitochondrial unfolded protein response controls cellular transcription and translation Kevin Klann1, J. Wade Harper2, Christian Münch1,2 1Institute of Biochemistry II, Goethe University Medical School, Frankfurt a.M., Germany; 2Department of Cell Biology, Harvard Medical School, Boston, USA
Maintenance of the mitochondrial proteome is critical for mitochondria's crucial role in metabolism and respiration. Consequently, perturbations in mitochondrial protein homeostasis are implicated in a wide range of human pathologies, including neurodegenerative diseases. However, how mitochondria respond to mitochondrial protein misfolding remains largely unclear and contains activation of the mitochondrial unfolded protein response (mtUPR) in an attempt to restore protein folding. The mammalian mtUPR is only poorly understood and involves a transcriptional response upregulating the mitochondrial folding machinery, including the mitochondrial chaperonins. We used quantitative multiplexed proteomics and RNA sequencing to study the cellular transcriptional and proteome responses to perturbations causing mtUPR. We found that mtUPR down-regulated the mitochondrial RNA processing machinery on mRNA and protein level. These effects led to accumulation of premature pre-RNA in mitochondria and a stop in mitochondrial translation, describing a new arm of the mammalian mtUPR. During recent analysis of changes in cellular translation (ribosome profiling) and proteome (quantitative mass spectrometry), we further identified specific signaling of the mtUPR outside mitochondria. Together, these mechanisms aid in gaining a molecular understanding of the mechanisms underlying the mtUPR and its role in human disease.
Funded by the DFG Emmy Noether Programme (C.M.), NIH grant R37NS083524 (J.W.H.), Biogen (J.W.H.), and an EMBO long-term fellowship (C.M.).
Credits: None available.
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