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Exercise Training, Mitochondrial Adaptations, and Aging
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Nashwa Cheema, Matthew Triolo, David A. Hood
Since synthesizing mitochondria is a coordinated effort between nuclear and mitochondrial gene products, an extravagant mechanism has evolved for the over 1,200 nuclear-encoded proteins that must enter the mitochondria. This is termed the protein import machinery (PIM) pathway (179). This PIM consists of the translocase of the outer membrane (TOM) complex and the translocase of the inner membrane (TIM) complex (179). Nuclear gene products destined for the mitochondria contain a mitochondrial-targeting sequence, which signals the pre-protein to the correct location within the mitochondria. These pre-proteins can be localized to various areas of the mitochondria depending on their targeting sequence. In general, matrix-bound proteins enter through the TOM complex and they are shuttled through the TIM complex via the chaperone mtHsp70. The newly imported proteins are then processed by mitochondrial processing peptidase (MPP), and they are refolded into a mature form with the aid of mitochondrial chaperones (121, 178, 179). This import machinery is critically important, as many disorders are associated with its dysfunction (106). Endurance training has been shown to increase the expression of PIM components and enhance the kinetics of protein import into the mitochondria (56, 84, 162). For example, Tfam import is accelerated by chronic exercise (56), and this serves to help coordinate the expression of mtDNA with that of nuclear gene expression.
Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Mohr-Tranebjaerg syndrome, also known as deafness-dystonia-optic neuronopathy (DDON) syndrome (Mohr and Mageroy, 1960) is inherited in X-linked recessive pattern, with some female carriers also showing signs of minor neuropathy and mild hearing impairment. DDP (deafness dystonia peptide) protein is involved in the import of nuclear-encoded mitochondrial proteins into the inner mitochondrial membrane (Wallace and Murdock, 1999). Except of deafness, other symptoms may include visual disability leading to cortical blindness, focal, segmental, or multifocal dystonia primarily in the upper body and with progressive generalization, fractures, cortical atrophy predominantly in the parieto-occipital cortex, and mental deficiency (Tranebjaerg et al., 1995). The dystonia with age of onset ranging from the first to the fourth decade tends to be focal, segmental, or multifocal at onset with progressive generalization (Ujike et al., 2001). Another protein linked with MTS is translocase of mitochondrial inner membrane 8A (TIMM8A). Mutation in TIMM8A also underlies a distinct disorder called Jensen syndrome (Tranebjaerg et al., 2001).
Passive heat stress induces mitochondrial adaptations in skeletal muscle
Published in International Journal of Hyperthermia, 2023
Erik D. Marchant, W. Bradley Nelson, Robert D. Hyldahl, Jayson R. Gifford, Chad R. Hancock
Aside from the apparent role of HSP72 in activating PGC-1α through AMPK and SIRT1, heat shock proteins play a vital role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix, as well as in helping fold and assemble them into complexes [52]. The mitochondrial proteome is composed of over 1,000 proteins, 99% of which are nuclear encoded, with only 13 being coded for by mitochondrial DNA [80]. Because most mitochondrial proteins are translated outside the mitochondria, specialized import machinery is required to introduce newly synthesized proteins into the mitochondrial matrix. Two primary players in this process are the translocase of the outer membrane (TOM), and the translocase of the inner membrane (TIM) [81]. Interestingly, both cytosolic and mitochondrial heat shock proteins are vital for this translocation process, partially due to their interactions with TIM and TOM [81–83]. Furthermore, once introduced into the mitochondria, heat shock protein 60 is necessary for the proper folding and assembly of the respiratory complexes of the electron transport system [84]. To date, it is unknown if passive heating in humans or animals improves protein import and folding due to increased HSP content or activation in skeletal muscle. However, the vital role of HSPs in mitochondrial protein import and assembly suggests that this is an important area for future research.
Mitochondria autophagy: a potential target for cancer therapy
Published in Journal of Drug Targeting, 2021
Yu-Han Qiu, Tian-Shu Zhang, Xiao-Wei Wang, Meng-yan Wang, Wen-Xia Zhao, Hui-Min Zhou, Cong-Hui Zhang, Mei-Lian Cai, Xiao-Fang Chen, Wu-Li Zhao, Rong-Guang Shao
PINK1 is a serine/threonine kinase, is a key inducer of mitophagy, and has a molecular weight of 63 kDa [87,88]. It is required for Ca2+ accumulation and mitochondrial membrane depolarisation in early stages of mitophagy as well as for the recognition and removal of depolarised mitochondria in later stages [89]. Generally, PINK1 enters the IMM through the translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM) complexes and is cleaved and degraded by proteases located on the IMM; thus, PINK1 is maintained at a low level under basal conditions [90,91].
Gut bacteria signaling to mitochondria in intestinal inflammation and cancer
Published in Gut Microbes, 2020
Dakota N. Jackson, Arianne L. Theiss
Mitochondria are double membrane-bound organelles found generally in large numbers in the cytoplasm of eukaryotic cells. Mitochondria are important organelles due to their primary function to generate energy for the cell in the form of adenosine 5′-triphosphate (ATP). In 1957, Phillip Skiekevitz coined the phrase “powerhouse of the cell” for the organelle. In addition to ATP production, mitochondria are an important site of intracellular calcium storage and the induction of apoptosis during cellular stress predominantly by the release of cytochrome c into the cytosol. The outer mitochondrial membrane (OMM) is composed of a phospholipid bilayer separating the mitochondria and its contents from the cytosol. Ions and proteins smaller than 5 kDa diffuse into and out of the mitochondria freely via porins, and therefore, the concentration of small proteins and ions in the mitochondrial intermembrane space matches the cytosol. Proteins larger than 5 kDa possessing a 5′ mitochondrial localization sequence translocate across the OMM via binding to translocase of the outer membrane (TOM) transporters. Proteins transferred into the mitochondria include nuclear DNA encoded proteins such as those for oxidative phosphorylation and heat shock proteins.1 The inner mitochondrial membrane (IMM) is also a phospholipid bilayer and houses electron transport chain (ETC) complexes which drive ATP production. Transporters called translocase of the inner membrane (TIMs) are required for all ions and proteins to enter the mitochondrial matrix2 allowing formation of the protein gradient in the space between the OMM and IMM, driving electron flow through the ETC.3 Inward folds of the IMM are called cristae, which increase the surface area for ATP production to match cellular demand.4 Within the IMM is the mitochondrial matrix which houses ribosomes, mitochondrial DNA (mtDNA), and ATP synthase proteins that facilitate the catalysis from adenosine diphosphate (ADP) to ATP.1