Selective degradation of mitochondria by mitophagy

Kim, Insil; Rodrı́guez-Enrı́quez, Sara; Lemasters, John J.

doi:10.1016/j.abb.2007.03.034

Cited by 1,409 publications

(1,117 citation statements)

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“…Mitochondria can be specific targets of this process through a selective process called mitophagy, which is critical for organelle quality control. 30,31 We hypothesized that increased autophagy could represent an adaptive and/or compensatory mechanism aimed at eliminating dysfunctional and damaged organelles in 13514A4G fibroblasts, thus mitigating the effect of the pathological mutation. To test this hypothesis, we monitored the rate of mitochondria degradation via autophagy by implementing the recently described technique based on the protein Keima.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, autophagy has been recognized as an important response to energetic defects, 49 as well as the leading mechanism for eliminating damaged organelles. 30,31 In addition, mitochondrial Ca 2+ signaling has a role in the regulation of autophagy. 6 This complex relationship could allow, in the context of a mitochondrial disorder, the triggering of a cellular response that compensate, at least in part, the energetic defect, dampening the clinical phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear-and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A4G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A4G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient. Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear-or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber's hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). 1,2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca 2+ homeostasis. 3,4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenot...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

et al. 2015

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“…[13][14][15][16] Because mitochondria are the crucial sources of ROS in aerobic eukaryotic cells, androgen deficiency in aged males may be attributed to dysfunctional mitochondria owing to an accumulation of ROS. [17][18][19] Autophagy is a cellular degradative pathway that involves the delivery of cytoplasmic cargo to lysosomes, and it is essential for cell survival, differentiation, development and homeostasis. [19][20][21] Autophagy can be induced by inhibiting target of rapamycin with rapamycin or blocked by inhibiting the class III PI3K with 3-methyladenine, wortmannin or bafilomycin A1 which inhibits the autophagosome fusion.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] Autophagy is a cellular degradative pathway that involves the delivery of cytoplasmic cargo to lysosomes, and it is essential for cell survival, differentiation, development and homeostasis. [19][20][21] Autophagy can be induced by inhibiting target of rapamycin with rapamycin or blocked by inhibiting the class III PI3K with 3-methyladenine, wortmannin or bafilomycin A1 which inhibits the autophagosome fusion. Autophagy can be measured by ultrastructural observation of autophagic compartments (such as the phagophore, autophagosome and autolysosome), by detecting the expression of Atg8-PE or microtubule-associated protein light chain 3 (LC3)-II biochemically or by observing the contribution of green fluorescent protein (GFP)-tagged Atg8 or LC3 microscopically.…”

Section: Introductionmentioning

confidence: 99%

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Li¹,

Chen²,

Chen³

et al. 2011

Asian J Androl

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Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males, but the mechanism remains unclear. In this study, we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity. Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production. In Leydig cells from young and aged rats, treatment with wortmannin, an autophagy inhibitor, inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production. In contrast, treatment with rapamycin, an autophagy activator, enhanced LH-stimulated steroidogenesis in Leydig cells from aged, but not young, rats. Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin. Furthermore, an increased level of ROS, induced by H 2 O 2 , resulted in LH-stimulated steroidogenic inhibition. Finally, knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells, which were associated with increased intracellular ROS level. These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells, which might be influenced by intracellular ROS levels.

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“…Mitophagy, which is the mitochondrial-specific form of this process, is important in the control of damaged or stressed cellular organelles. The process appears to be upregulated after alterations in mitochondrial membrane permeability [253]. Parkin is selectively recruited from the cytosol to the mitochondria with low membrane potential, where it mediates the degradation of the impaired organelle [254].…”

Section: Pink1 and Parkinmentioning

confidence: 99%

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2013

Free Radical Biology and Medicine

100

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a b s t r a c tParkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of a-synuclein (a-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to a-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves a-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.

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Selective degradation of mitochondria by mitophagy

Cited by 1,409 publications

References 73 publications

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

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