Oxidative stress causes reversible changes in mitochondrial permeability and structure

Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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“…26 Apoptosis underlies neurodegeneration in dYME1L del flies. Mitochondrial dysfunction has been reported to trigger apoptosis in mammals.…”

Section: Resultsmentioning

confidence: 99%

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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“…Fibroblasts from patients with genetic mtDNA defects demonstrated that severe complex I deficiency yield increased ROS production was associated with mitochondrial fragmentation (79). Similarly, exposure of cultured cells to sublethal doses of exogenous ROS (H 2 O 2 ) induced mitochondrial fragmentation in mouse embryonic fibroblasts (MEFs) (31,73,92), neuronal cells (71), and in C 2 C 12 myocytes (47). …”

Section: Or Possibly By Other Nonmorphological Factors (See Altering mentioning

confidence: 99%

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Picard

Shirihai

Gentil

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

268

193

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In response to cellular and environmental stresses, mitochondria undergo morphology transitions regulated by dynamic processes of membrane fusion and fission. These events of mitochondrial dynamics are central regulators of cellular activity, but the mechanisms linking mitochondrial shape to cell function remain unclear. One possibility evaluated in this review is that mitochondrial morphological transitions (from elongated to fragmented, and vice-versa) directly modify canonical aspects of the organelle's function, including susceptibility to mitochondrial permeability transition, respiratory properties of the electron transport chain, and reactive oxygen species production. Because outputs derived from mitochondrial metabolism are linked to defined cellular signaling pathways, fusion/fission morphology transitions could regulate mitochondrial function and retrograde signaling. This is hypothesized to provide a dynamic interface between the cell, its genome, and the fluctuating metabolic environment. mitochondrial dynamics; morphology; fusion and fission; bioenergetics; retrograde signaling MITOCHONDRIA are crucial organelles involved in cellular energy production and in the regulation of numerous aspects of cellular activity, including, but not limited to, apoptosis, Ca 2ϩ signaling, and redox homeostasis (41). Over the last decade, mitochondria have moved to the forefront of cell biology research for their ability to undergo regulated events of membrane fusion and fission, which remodel the architecture of the mitochondrial network within the cytoplasm (43,36,146). Processes of mitochondrial fusion and fission are collectively termed mitochondrial dynamics. Importantly, abnormal mitochondrial dynamics cause bioenergetic defects (26), induce embryonic lethality in transgenic animal models (27), and underly a heterogenous group of human diseases (164), attesting to the pivotal role of these processes in physiopathology (25,50,91). In addition, experimental work has shown that mitochondrial dynamics are involved in regulating cellular activity and that mitochondria participate in important cellular signaling pathways (136,158).Mitochondrial retrograde signaling is defined as the transfer of information from mitochondria to the cytoplasm and nucleus. Retrograde signaling pathways have been established to occur in response to metabolic perturbations, with the aim to trigger adaptive cellular responses orchestrated by coordinated changes in gene expression (reviewed in Refs. 21 and 93). Among the retrograde signals produced by mitochondria that are known to regulate different aspects of cellular activity, the most studied include reactive oxygen species (ROS), pro-apoptotic molecules, ATP/ADP/AMP, metabolic intermediates (NAD ϩ /NADH), and Ca 2ϩ (20,39,58). From recent discoveries revealing that mitochondrial dynamics regulate cellular activity in response to various stressors, it is hypothesized that changes in mitochondrial morphology regulate, either directly or indirectly, various aspects of mitochondrial funct...

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“…Cells were transiently transfected with Fugene 6 (Roche Applied Science) and incubated for 16 -30 h at 37°C. Staining of cells was performed as described (24). Cells were fixed in 3.7% formaldehyde for 20 -30 min at room temperature in 0.1 M sodium phosphate, pH 7.2, 150 mM NaCl.…”

Section: Expression Of Mouse Msra In Escherichia Coli and Hek293mentioning

confidence: 99%

“…M8032) until no color change occurred. Immunofluorescence staining was performed as described (24). Antibodies to MsrA (1:1000) and cytochrome c (1:500) were used for cell staining.…”

Section: Expression Of Mouse Msra In Escherichia Coli and Hek293mentioning

confidence: 99%

Dual Sites of Protein Initiation Control the Localization and Myristoylation of Methionine Sulfoxide Reductase A

Kim

Cole

Lim

et al. 2010

Journal of Biological Chemistry

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Methionine sulfoxide reductase A is an essential enzyme in the antioxidant system, which scavenges reactive oxygen species through cyclic oxidation and reduction of methionine and methionine sulfoxide. In mammals, one gene encodes two forms of the reductase, one targeted to the cytosol and the other to mitochondria. The cytosolic form displays faster mobility than the mitochondrial form, suggesting a lower molecular weight for the former. The apparent size difference and targeting to two cellular compartments had been proposed to result from differential splicing of mRNA. We now show that differential targeting is effected by use of two initiation sites, one of which includes a mitochondrial targeting sequence, whereas the other does not. We also demonstrate that the mass of the cytosolic form is not less than that of the mitochondrial form; the faster mobility of cytosolic form is due to its myristoylation. Lipidation of methionine sulfoxide reductase A occurs in the mouse, in transfected tissue culture cells, and even in a cell-free protein synthesis system. The physiologic role of myristoylation of MsrA remains to be elucidated.All organisms living in an aerobic atmosphere are subjected to oxidative stress from reactive oxygen and nitrogen species. Proteins are a notable target of these species, and mechanisms have evolved to intercept them and to cope with proteins that do undergo oxidative modification (1). If the covalent modification is not reversible then the protein is targeted for selective degradation. Repair systems have evolved to cope with the reversible modifications, including oxidation and reduction of the sulfur-containing amino acids cysteine and methionine. The latter is relatively readily oxidized to methionine sulfoxide (MetO).2 Virtually all organisms from bacteria to mammals have several methionine sulfoxide reductases (Msr), which catalyze the reduction of MetO to Met (2). Reduction of methionine residues in proteins allows them to react again with reactive species, creating a system with catalytic efficiency in scavenging potentially damaging species. Thioredoxin and thioredoxin reductase act sequentially to regenerate active Msr, with the net result being the catalytic scavenging of reactive oxygen species at the expense of NADPH. A scheme of the system is shown in Fig. 1 Oxidation of Met to MetO creates a chiral center, and the Sand R-epimers are substrates for specific Msr (2, 4). In most organisms, the S-epimer is reduced by MsrA, and the R-epimer is reduced by MsrB, both using thioredoxin as the source of reducing equivalents. MsrA was described well before MsrB so that the majority of the studies in the literature were performed with MsrA. Those studies provide strong evidence supporting the physiological importance of cyclic oxidation and reduction of Met residues. Knocking out MsrA caused increased susceptibility to oxidative stress in mice (5), yeast (6), and bacteria (7-9). Conversely, overexpressing MsrA conferred increased resistance to Drosophila (10), Saccharomyces (11), ...

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Oxidative stress causes reversible changes in mitochondrial permeability and structure

Cited by 28 publications

References 26 publications

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Dual Sites of Protein Initiation Control the Localization and Myristoylation of Methionine Sulfoxide Reductase A

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