Abstract
Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.
Highlights
Mitochondria are double membrane, dynamic, and semiautonomous organelles which have several critical cellular functions
We mainly focus on the role of chaperones, proteases, ubiquitin-proteasome system (UPS), mitochondria-derived vesicles (MDV), mitochondrial unfolded protein response (UPRmt ), and mitophagy in assisting correct protein folding, removal of misfolded or aggregated proteins and clearance of dysfunctional mitochondria, thereby ensuring the maintenance of mitochondrial health
ER, endoplasmic reticulum; TOM, translocase of the outer membrane; TIM, translocase of the inner membrane; UPS, ubiquitin-proteasome degradation system; mitochondrial precursor over-accumulation stress” (mPOS), mitochondrial precursor over-accumulation stress; UPRam, unfolded protein response activated by mistargeting of proteins; MDV, mitochondria-derived vesicles; PINK1, phosphatase and tensin homolog (PTEN)-induced kinase; PARKIN, E3 ubiquitin-protein ligase parkin; U, Ubiquitin; UPRmt, mitochondrial unfolded protein response; iAAA, inner membrane-embedded AAA protease; mAAA, matrix-embedded AAA protease; Mitochondrial intermediate peptidase (MIP), mitochondrial intermediate presequence protease; MPP, matrix processing peptidase; Overlapping with the m-AAA protease 1 homolog (OMA1), overlapping activity with m -AAA protease; HTRA2, High-temperature requirement protein A2; CoQ, Coenzyme Q; LON, Lon protease; CLPX, ATP-dependent Clp protease proteolytic subunit X; CLPP, ATP-dependent Clp protease proteolytic subunit P; Mito-Ribosome, Mitochondrial Ribosome
Summary
Mitochondria are double membrane, dynamic, and semiautonomous organelles which have several critical cellular functions. Previous evidence supports that mitochondria evolved from the engulfment of an α-proteobacterium by a pre-eukaryotic progenitor cell and comprised of the outer (OMM) and inner mitochondrial membranes (IMM) which invaginate to form the cristae [6]. These phospholipid bilayer membranes separate the intermembrane space (IMS) from the matrix [1,6,7,8]. The mtDNA encoded proteins are hydrophobic membrane subunits of the electron transport chain (ETC) These proteins synthesized at the membrane-anchored mitochondrial ribosomes, which allow the direct integration of nascent proteins into the IMM [14,15]. Studying the molecular mechanisms of mitochondrial protein quality control will help to understand the pathways for therapeutic targeting in numerous disease conditions
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