Mitochondrial quality control: an integrated network of pathways

Fischer, Fabian; Hamann, Andréa; Osiewacz, Heinz D.

doi:10.1016/j.tibs.2012.02.004

Cited by 204 publications

(189 citation statements)

References 79 publications

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“…A number of groups (17,25,35) have recently demonstrated a close connection between autophagy and mitochondrial turnover. Mitochondrial quality control is the process whereby mitochondria undergo successive rounds of fusion and fission with a dynamic exchange of components to segregate functional and damaged elements (16). Removal of a damaged mitochondrion is accomplished via mitophagy (12).…”

Section: Discussionmentioning

confidence: 99%

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

169

120

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Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1␣ and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stressinduced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1␣-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1␣-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.Bcl-2/adenovirus E1B 19 kDa-interacting protein-3; acute kidney injury; autophagy; mitophagy; sestrin-2 ISCHEMIA is the leading cause of acute kidney injury (AKI) in the adult population. Prominent morphological features of ischemic AKI include effacement and loss of the proximal tubule brush border, patchy loss of tubular cells, focal areas of proximal tubular dilation, and increased apoptosis (9). The mechanisms that dictate the survival or death of renal cells under oxidative stress must be more completely understood before novel therapeutic strategies for the treatment of ischemic AKI can be explored. Proximal renal tubular cells have high rates of ATP consumption and are very sensitive to hypoxia; thus, mitochondrial damage is one of the most important factors in determining the survival of these cells (1,43).Autophagy is one of the cellular processes that protect cells from genotoxic stress, oxidative stress, accumulation of misfolded proteins, and nutrient deprivation. We (20) have previously reported results from a study of autophagy in a mouse model of AKI. Autophagy plays roles in the pathogenesis of many diseases, and, in kidney disease, both beneficial and detrimental effects of autophagy have been reported (19 -22). Our understanding of autophagy has expanded greatly in recent years, largely due to the identification...

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Section: Discussionmentioning

confidence: 99%

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Imamura

Urushido

Hamada

et al. 2013

American Journal of Physiology-Renal Physiology

169

120

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“…Mitochondrial quality control occurs at the level of organelle and protein integrity and is carried out via mechanisms that identify the compromised components and marks them for destruction, followed by the subsequent recruitment of the machinery responsible for their degradation [11,13,[110][111][112][113]. Quality control of mitochondrial proteins is described in detail elsewhere (e.g.…”

Section: Mitochondrial Degradationmentioning

confidence: 99%

“…Quality control of mitochondrial proteins is described in detail elsewhere (e.g. [11,114]). The specific degradation of dysfunctional mitochondria ("mitophagy") is carried out by the lysosomal-autophagic machinery after the dysfunctional organelles have been marked for destruction.…”

Section: Mitochondrial Degradationmentioning

confidence: 99%

“…In this sense, (progressive) mitochondrial dysfunction has not only been linked to (relatively rare) metabolic disorders but also to normal human aging, neurodegeneration, cancer, diabetes and metabolic syndrome (e.g. [4,5,[11][12][13][14][15][16]). Although mitochondria display a certain genetic and metabolic autonomy, their function is intricately linked to cellular physiology at the level of ion/metabolite exchange and (retrograde) signaling cascades [10,17].…”

Section: Introductionmentioning

confidence: 99%

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Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Tronstad¹,

Nooteboom²,

Nilsson³

et al. 2014

CPD

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Running title: Regulation and quantification of mitochondrial morphology and content. Word count: 15,454 (total)Characters: 107,091 (including spaces); 92,067 (excluding spaces) Keywords: mitochondrial biogenesis, mitochondrial dynamics, mitochondrial degradation, living cells, TMRM, microscopy, segmentation, image analysis.Page 2 of 37 ABSTRACTMitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

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“…All pathways are limited in their capacity of dealing with different types of mitochondrial damage and thus, after passing certain thresholds, pathways of a higher order become activated [11,[20][21][22][23][24][25][26]. The precise regulation mechanisms of the corresponding links and interactions remain to be established.…”

Section: Introductionmentioning

confidence: 99%

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

2013

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Maintenance of functional mitochondria is essential in order to prevent degenerative processes leading to disease and aging. Mitochondrial dynamics plays a crucial role in ensuring mitochondrial quality but may also generate and spread molecular damage through a population of mitochondria. Computational simulations suggest that this dynamics is advantageous when mitochondria are not or only marginally damaged. In contrast, at a higher degree of damage, mitochondrial dynamics may be disadvantageous. Deceleration of fusion‐fission cycles could be one way to adapt to this situation and to delay a further decline in mitochondrial quality. However, this adaptive response makes the mitochondrial network more vulnerable to additional molecular damage. The “mitochondrial infectious damage adaptation” (MIDA) model explains a number of inconsistent and counterintuitive data such as the “clonal expansion” of mutant mitochondrial DNA. We propose that mitochondrial dynamics is a double‐edged sword and suggest ways to test this experimentally.

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Mitochondrial quality control: an integrated network of pathways

Cited by 204 publications

References 79 publications

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

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