Autophagy in health and disease. 5. Mitophagy as a way of life

Gottlieb, Roberta A.; Carreira, Raquel

doi:10.1152/ajpcell.00097.2010

Cited by 216 publications

(170 citation statements)

References 108 publications

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“…Prolonged deficits in bioenergetics together with elevated oxidative stress lead to activation of apoptotic pathways, impaired mitophagy, and, ultimately, neuronal death [143]. Mitochondrial autophagy, often referred to as mitophagy, is a highly dynamic process for disposal and recycling of unhealthy mitochondria [143].…”

Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

“…Mitochondrial autophagy, often referred to as mitophagy, is a highly dynamic process for disposal and recycling of unhealthy mitochondria [143]. A balance between mitophagy and mitochondrial biogenesis provides an efficient energy transducing system required for neuronal survival [144], whereas mitochondrial dysfunction contributes to neuronal death and AD pathology (Fig.…”

Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

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Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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“…Clearance of dysfunctional or aged mitochondria by mitophagy plays an essential role in the anti-ageing process. [24][25][26] and many age-related pathologies. [27][28][29] In this report, we studied the role of autophagy in regulating androgen production in Leydig cells from aged rats.…”

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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“…Our understanding of autophagy has expanded greatly in recent years, largely due to the identification of the many genes involved and to the development of improved methods to monitor the process, such as green fluorescent protein (GFP)-light chain 3 (LC3) to visualize autophagosomes in vivo (28). A number of groups (17,25,35) have demonstrated a close connection between autophagy and mitochondrial turnover. Removal of mitochondria that contain damaged components is accomplished via autophagy (mitophagy).…”

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confidence: 99%

“…BNIP3 contains a single Bcl-2 homology 3 domain and is localized primarily in the mitochondria (6,11,24,48). Overexpression of BNIP3 has been reported to induce mitophagy by triggering mitochondrial depolarization (13,17,42). However, little is known of the function of BNIP3 and mitophagy in renal tubular cells.…”

mentioning

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

175

125

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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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Autophagy in health and disease. 5. Mitophagy as a way of life

Cited by 216 publications

References 108 publications

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

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

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

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