Journal Article

Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation

Münch, Christian, Harper, J. Wade

2016

Overview

Acute protein folding stress in the mitochondrial matrix activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition. Mammalian mitochondrial stress responses The mitochondrial unfolded protein response (UPR mt ) pathway has been studied in detail in the Caenorhabditis elegans roundworm, where it has been shown to sense protein misfolding within the mitochondrial matrix and to induce a program of nuclear gene expression to counteract this stress. How mammalian cells respond to unfolded matrix proteins has remained much less clear. Christian Münch and Wade Harper used pharmacological inhibitors to induce acute protein folding stress in the mitochondrial matrix, and performed transcriptional and quantitative proteomic analysis to examine the response of mammalian cells. They observed widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. This was accompanied by a rapid reduction in the matrix-localized protein synthesis through translational inhibition. The work could spur further investigation of the mammalian UPR mt . The mitochondrial matrix is unique in that it must integrate the folding and assembly of proteins derived from the nuclear and mitochondrial genomes. In Caenorhabditis elegans , the mitochondrial unfolded protein response (UPR mt ) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis 1 , 2 , 3 . While misfolded mitochondrial-matrix-localized ornithine transcarbamylase induces chaperonin expression 4 , 5 , 6 , our understanding of mammalian UPR mt is rudimentary 7 , reflecting a lack of acute triggers for UPR mt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPR mt on mitochondrial translation to control protein folding loads. Here we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 (ref. 8 ) or LON protease 9 , which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPR mt . This response encompasses widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing caused by transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3 (ref. 10 ). This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPR mt .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/89 / 38/77 / 38/89 / 38/90 / 38/91 / 631/45/470 / 631/45/500 / 631/45/612/1240 / 631/80/470 / 631/80/642/333 / 82/58 / 96/106 / Biological research / Biology, Experimental / Caenorhabditis elegans / Cell Nucleus - genetics / Chaperonins - metabolism / Down-Regulation / Genes / Genetic aspects / Homeostasis / Humanities and Social Sciences / Humans / letter / Mammals / Mitochondria / Mitochondria - drug effects / Mitochondria - genetics / Mitochondria - metabolism / Mitochondrial DNA / Mitochondrial Proteins - biosynthesis / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Molecular chaperones / multidisciplinary / Ornithine Carbamoyltransferase - metabolism / Protein biosynthesis / Protein Biosynthesis - drug effects / Protein Folding / Protein research / Protein synthesis / Proteome - biosynthesis / Proteome - genetics / Proteome - metabolism / Ribonuclease P - metabolism / Ribonucleic acid / RNA / RNA Precursors - genetics / RNA Precursors - metabolism / RNA Processing, Post-Transcriptional / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Transcription factors / Unfolded Protein Response - drug effects / Unfolded Protein Response - genetics