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Proteins embedded in the inner mitochondrial membrane (IMM) perform essential cellular functions. Maintaining the folding state of these proteins is therefore of the utmost importance, and this is ensured by IMM chaperones and proteases that refold and degrade unassembled and misfolded proteins. However, the physiological consequences specific to IMM protein misfolding remain obscure because deletion of these chaperones/proteases (the typical experimental strategy) often affects many mitochondrial processes other than protein folding and turnover. Thus, novel experimental systems are needed to evaluate the direct effects of misfolded protein on the membrane. Such a system has been developed in recent years. Studies suggest that numerous pathogenic mutations in isoform 1 of adenine nucleotide translocase (Ant1) cause its misfolding on the IMM. In this review, we first discuss potential mechanisms by which dominant Ant1 mutations may cause disease, highlighting IMM protein misfolding, per se, as a likely pathological factor. Then we discuss the intramitochondrial effects of Ant1 misfolding such as IMM proteostatic stress, respiratory chain dysfunction, and mtDNA instability. Finally, we summarize the mounting evidence that IMM proteostatic stress can perturb mitochondrial protein import to cause the toxic accumulation of mitochondrial proteins in the cytosol: a cell stress mechanism termed mitochondrial Precursor Overaccumulation Stress (mPOS).
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The voltage difference, normally maintained at approximately -180mV, across the INNER MITOCHONDRIAL MEMBRANE, by a net movement of positive charge across the membrane. It is a major component of the PROTON MOTIVE FORCE in MITOCHONDRIA used to drive the synthesis of ATP.
A multi-domain mitochondrial membrane protein and member of the bcl-2 Protein family. Bak protein interacts with TUMOR SUPPRESSOR PROTEIN P53 and promotes APOPTOSIS.
A ubiquitous membrane transport protein found in the plasma membrane of diverse cell types and tissues, and in nuclear, mitochondrial, and Golgi membranes. It is the major integral transmembrane protein of the erythrocyte plasma membrane, comprising 25% of the total membrane protein. It exists as a dimer and performs the important function of allowing the efficient transport of bicarbonate across erythrocyte cell membranes in exchange for chloride ion.
The two lipoprotein layers in the MITOCHONDRION. The outer membrane encloses the entire mitochondrion and contains channels with TRANSPORT PROTEINS to move molecules and ions in and out of the organelle. The inner membrane folds into cristae and contains many ENZYMES important to cell METABOLISM and energy production (MITOCHONDRIAL ATP SYNTHASE).
Mitochondrial anion carrier proteins that function as dimers and form proton channels in the INNER MITOCHONDRIAL MEMBRANE which creates proton leaks and uncouples OXIDATIVE PHOSPHORYLATION from ATP synthesis, resulting in the generation of heat instead of ATP.
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