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Hui Jiang’s laboratory discovers mitochondrial stress responses maintain mitochondrial membrane potential in OXPHOS mutants

Publication Date:2021/03/19
On March 3, 2020 ---- Dr. Hui Jiang’s laboratory of National Institute of Biological Sciences, Beijing/Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR) published a new research article titled “OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential” online in EMBO Reports. The new study in yeast reveals maintaining mitochondrial membrane potential is a major function of mitochondrial stress responses and has characterized the major stress response pathways and the effectors.

Mitochondria are the central hub of cellular metabolism and energy production. Energy released by mitochondrial respiration pumps protons to establish membrane potential (ΔΨm) across mitochondrial inner membrane. ΔΨm powers ATP synthesis, drives import of mitochondrial protein precursors, and facilitates transport of some metabolites across inner membrane. One of the indispensable functions of mitochondria is to synthesize iron-sulfur cluster (ISC). ISCs are synthesized in mitochondrial matrix and incorporated into ISC-containing enzymes, including house-keeping enzymes such as DNA polymerases and ribosome recycling factors. ΔΨm is required for the import of ISC synthesis enzymes and transport of Fe2+ into matrix. Thus,ΔΨm is indispensable for cell viability and proliferation.

It has been known that OXPHOS-deficient mitochondria import and hydrolyze ATP to maintain ΔΨm. OXPHOS deficiency also activates mitochondrial stress responses in various organisms. But whether mitochondrial stress responses participate in m maintenance remain unclear. Researchers in Hui Jiang’s lab generated yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA (0) respectively. They observed that these mutants have increasing stresses and progressive reduction of ΔΨm. RNAseq and mitochondrial proteome analyses of these mutants show that these mutants progressively activate adaptive responses: (1) all the mutants downregulate the transcription of ATP synthase inhibitor Inh1 to enhance the ATP hydrolysis activity of mitochondria; (2) in V and 0 cells with low ΔΨm, cells activate AMPK/Snf1 to enhance glycolysis and repress ribosome biogenesis. This response optimizes cellular energy metabolism to maximize ATP supply to mitochondria; (3) V and 0 cells also hyper-phosphorylates Puf3 --- a mRNA binding protein that associates with hundreds of mRNAs encoding mitochondrial proteins. Puf3 hyper-phosphorylation upregulates Puf3-associated mRNAs to promote mitochondrial biogenesis. Among the hundreds of Puf3 substrates, upregulation of the import receptor Mia40 is the key to maintain ΔΨm. Abolishing these responses, such as blocking Inh1 downregulation, P0 cells fail to maintainΔΨm and ISC synthesis, resulting in growth arrest and cell death. Taken together, OXPHOS-deficient cells activate multiple adaptive responses to maintain ΔΨm, ISC synthesis, and cell viability and proliferation.

In human mitochondrial diseases, pathogenic mutations of more than 150 genes cause OXPHOS impairment, which is often accompanied by ΔΨm reduction. Considering the yeast effector proteins to maintain ΔΨm are highly conserved in human, this study provides clues for therapeutic strategies of human mitochondrial diseases.

Siqi Liu is the first author of this paper. Dr. Hui Jiang is the corresponding author. Other contributors include Shanshan Liu, Baiyu He, Dr. Lanlan Li, Dr. Lin Li, Dr. She Chen, Dr. Jiawen Wang, and Dr. Tao Cai. The research is supported by Beijing Municipal Science and Technology Commission.