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2012 Jun 29. doi: 10.1038/cdd.2012.81. [Epub ahead of print] [Available free: 2012 June 29, Cell Death & Differentiation

The pathways of mitophagy for quality control and clearance of mitochondria.

Source

1] FM Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115, USA [2] Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

Abstract

Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.Cell Death and Differentiation advance online publication, 29 June 2012; doi:10.1038/cdd.2012.81.

PMID:
22743996
[PubMed - as supplied by publisher]

 

2011 Jul 28;9:123.

Liver mitochondrial dysfunction is reverted by insulin-like growth factor II (IGF-II) in aging rats.

Source

Department of Physiology, School of Medicine, University of Málaga, 29071 Málaga, Spain.

Abstract

BACKGROUND:

Serum IGF-I and IGF-II levels decline with age. IGF-I replacement therapy reduces the impact of age in rats. We have recently reported that IGF-II is able to act, in part, as an analogous of IGF-I in aging rats reducing oxidative damage in brain and liver associated with a normalization of antioxidant enzyme activities. Since mitochondria seem to be the most important cellular target of IGF-I, the aim of this work was to investigate whether the cytoprotective actions of IGF-II therapy are mediated by mitochondrial protection.

METHODS:

Three groups of rats were included in the experimental protocol young controls (17 weeks old); untreated old rats (103 weeks old); and aging rats (103 weeks old) treated with IGF-II (2 μg/100 g body weight and day) for 30 days.

RESULTS:

Compared with young controls, untreated old rats showed an increase of oxidative damage in isolated mitochondria with a dysfunction characterized by: reduction of mitochondrial membrane potential (MMP) and ATP synthesis and increase of intramitochondrial free radicals production and proton leak rates. In addition, in untreated old rats mitochondrial respiration was not blocked by atractyloside. In accordance, old rats showed an overexpression of the active fragment of caspases 3 and 9 in liver homogenates. IGF-II therapy corrected all of these parameters of mitochondrial dysfunction and reduced activation of caspases.

CONCLUSIONS:

The cytoprotective effects of IGF-II are related to mitochondrial protection leading to increased ATP production reducing free radical generation, oxidative damage and apoptosis.

PMID:
21798010
[PubMed - indexed for MEDLINE]
PMCID:
PMC3162510

 

2011 Oct 1;51(7):1289-301. Epub 2011 Jul 6.

Cross talk between mitochondria and NADPH oxidases. [Have full paper]

Source

Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA. sergey.dikalov@vanderbilt.edu

Abstract

Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21777669
[PubMed - indexed for MEDLINE]
PMCID:
PMC3163726

 

2012 Jun;34(3):681-92. Epub 2011 May 26.

Melatonin protects lung mitochondria from aging.

Source

Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Spain.

Abstract

We assessed whether melatonin administration would prevent the hyperoxidative status that occurs in lung mitochondria with age. Mitochondria from lungs of male and female senescent prone mice at 5 and 10 months of age were studied. Age-dependent mitochondrial oxidative stress was evaluated by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and reductase activities. Mitochondrial respiratory chain and oxidative phosphorylation capability were also measured. Age induces a significant oxidative/nitrosative status in lung mitochondria, which exhibited a significantly reduced activity of the respiratory chain and ATP production. These manifestations of age were more pronounced in males than in females. After 9 months of melatonin administration in the drinking water, the hyperoxidative status and functional deficiency of aged lung mitochondria were totally counteracted, and had increased ATP production. The beneficial effects of melatonin were generally similar in both mice genders. Thus, melatonin administration, as a single therapy, maintained fully functioning lung mitochondria during aging, a finding with important consequences in the pathophysiology of lung aging. In view of these data melatonin, the production of which decreases with age, should be considered a preventive therapy against the hyperoxidative status of the aged lungs, and its use may lead to the avoidance of respiratory complications in the elderly.

PMID:
21614449
[PubMed - indexed for MEDLINE]
PMCID:
PMC3337938
[Available on 2013/6/1]

2010 May;48(4):297-310.

Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease.

Source

Department of Biochemistry and Molecular Biology, CNR Institute of Biomebranes, Bioenergetics University of Bari, Italy. g.paradies@biologia.uniba.it <g.paradies@biologia.uniba.it>

Abstract

Melatonin is a natural occurring compound with well-known antioxidant properties. Melatonin is ubiquitously distributed and because of its small size and amphiphilic nature, it is able to reach easily all cellular and subcellular compartments. The highest intracellular melatonin concentrations are found in mitochondria, raising the possibility of functional significance for this targeting with involvement in situ in mitochondrial activities. Mitochondria, the powerhouse of the cell, are considered to be the most important cellular organelles to contribute to degenerative processes mainly through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage to mitochondrial proteins, lipids and DNA. Therefore, protecting mitochondria from oxidative damage could be an effective therapeutic strategy against cellular degenerative processes. Many of the beneficial effects of melatonin administration may depend on its effect on mitochondrial physiology. Cardiolipin, a phospholipid located at the level of inner mitochondrial membrane is known to be intimately involved in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis. Alterations to cardiolipin structure, content and acyl chain composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological situations and aging. Recently, melatonin was reported to protect the mitochondria from oxidative damage by preventing cardiolipin oxidation and this may explain, at least in part, the beneficial effect of this molecule in mitochondrial physiopathology. In this review, we discuss the role of melatonin in preventing mitochondrial dysfunction and disease.

PMID:
20433638
[PubMed - indexed for MEDLINE]

2009 Oct;41(10):1989-2004. Epub 2009 Apr 5.

Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease.

Source

Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX 78249, USA. aliev03@gmail.com

Abstract

Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense "hypoxic" mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.

PMID:
19703659
[PubMed - indexed for MEDLINE]

2008 Oct;11(5):935-43.

Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection.

Source

Department of Biochemistry and Molecular Biology, CNR Institute of Biomembranes and Bioenergetics, University of Bari, Bari Italy.

Abstract

Reactive oxygen species (ROS) are considered a key factor in brain aging process. Complex I of the mitochondrial respiration chain is an important site of ROS production and hence a potential contributor to brain functional changes with aging. Appropriate antioxidant strategies could be particularly useful to limit this ROS production and associated mitochondrial dysfunction. Melatonin has been shown to possess antioxidant properties and to reduce oxidant events in brain aging. The mechanism underlying this protective effect of melatonin is not well established. In the present study, we examined the effects of long-term treatment of aged rats with melatonin on various parameters related to mitochondrial bioenergetics in brain tissue. After isolation of mitochondria from control, aged, and melatonin-treated young and aged rats, various bioenergetic parameters were evaluated such as complex I activity, rates of state 3 respiration, mitochondrial hydrogen peroxide (H2O2) production, and membrane potential. The mitochondrial content of normal and oxidized cardiolipin was also evaluated. We found that all these mitochondrial parameters were significantly altered with aging, and that melatonin treatment completely prevented these age-related alterations. These effects appear to be due, at least in part, to melatonin's ability to preserve the content and structural integrity of cardiolipin molecules, which play a pivotal role in mitochondrial bioenergetics. The melatonin's ability to prevent complex I dysfunction and cardiolipin peroxidation was also demonstrated by in vitro experiments on brain mitochondria treated with tert-butyl hydroperoxide. In summary, this study documents a decline of mitochondrial bioenergetic functions in brain with aging and the beneficial effect of melatonin.

PMID:
18928424
[PubMed - indexed for MEDLINE]

 

2009 Jan;72(1):29-33. Epub 2008 Sep 11. [Have full paper]

The "rejuvenatory" impact of lipoic acid on mitochondrial function in aging rats may reflect induction and activation of PPAR-gamma coactivator-1alpha.

Source

Oasis of Hope Hospital, Tijuana, Mexico. mccarty@pantox.com

Abstract

In aging rats, lipoic acid exerts a "rejuvenative" impact on mitochondria in various tissues, boosting mitochondrial membrane potential and oxygen consumption, while decreasing mitochondrial production of oxidants. A likely explanation for this phenomenon is that the mitochondria in aging rodents are structurally and functionally impaired by excessive oxidant stress - and that lipoic acid reverses this damage by amplifying key antioxidant mechanisms that protect mitochondria. A likely mediator of this effect is PPARgamma coactivator-1alpha (PGC-1alpha), which recently has been shown to promote transcription of the manganese-dependent superoxide dismutase, uncoupling protein-2, and an array of other proteins which provide antioxidant protection to mitochondria. Lipoic acid has been reported to activate both p38 MAP kinase and AMP-activated kinase (AMPK); p38 MAP kinase can boost the transcription, half-life, and coactivational activity of PGC-1alpha, and AMPK is known to promote its transcription in skeletal muscle and endothelial cells. Thus, it is intriguing to speculate that the remarkable antioxidant effects of lipoic acid therapy reflect not only induction of phase 2 antioxidants (e.g. glutathione and heme oxygenase-1), but also induction of various proteins that function expressly to protect mitochondria from self-generated oxidant stress. Further research is required to evaluate this model.

2008 Sep;43(9):813-9. Epub 2008 Jul 9. [Have full paper]

Mitochondrial biogenesis and healthy aging.

Source

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC, Carretera de Utrera Km 1, 41013 Sevilla, Spain.

Abstract

Aging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan. Mitochondria are particularly susceptive to damage over time as they are the major bioenergetic machinery and source of oxidative stress in cells. Effective control of mitochondrial biogenesis and turnover, therefore, becomes critical for the maintenance of energy production, the prevention of endogenous oxidative stress and the promotion of healthy aging. Multiple endogenous and exogenous factors regulate mitochondrial biogenesis through the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Activators of PGC-1alpha include nitric oxide, CREB and AMPK. Calorie restriction (CR) and resveratrol, a proposed CR mimetic, also increase mitochondrial biogenesis through activation of PGC-1alpha. Moderate exercise also mimics CR by inducing mitochondrial biogenesis. Negative regulators of PGC-1alpha such as RIP140 and 160MBP suppress mitochondrial biogenesis. Another mechanism involved in mitochondrial maintenance is mitochondrial fission/fusion and this process also involves an increasing number of regulatory proteins. Dysfunction of either biogenesis or fission/fusion of mitochondria is associated with diseases of the neuromuscular system and aging, and a greater understanding of the regulation of these processes should help us to ultimately control the aging process.

2008 May;149(5):2620-7. Epub 2008 Feb 14.

Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats.

Source

Department of Medical Physiology, School of Medicine, University CEU-Universidad San Pablo, Boadilla del Monte, 28668, Madrid, Spain.

Abstract

Serum IGF-I levels decline with age. We have recently reported that in aging rats the exogenous administration of IGF-I restores IGF-I circulating levels and age related-changes, improving glucose and lipid metabolisms, increasing testosterone levels and serum total antioxidant capability, and reducing oxidative damage in the brain and liver associated with a normalization of antioxidant enzyme activities. Understanding that mitochondria are one of the most important cellular targets of IGF-I, the aims of this study were to characterize mitochondrial dysfunction and study the effect of IGF-I therapy on mitochondria, leading to cellular protection in the following experimental groups: young controls, untreated old rats, and aging rats treated with IGF-I. Compared with young controls, untreated aging rats showed an increase of oxidative damage in isolated mitochondria with a mitochondrial dysfunction characterized by: depletion of membrane potential with increased proton leak rates and intramitochondrial free radical production, and a significant reduction of ATPase and complex IV activities. In addition, mitochondrial respiration from untreated aging rats was atractyloside insensitive, suggesting that the adenine nucleotide translocator was uncoupled. The adenine nucleotide translocator has been shown to be one of the most sensitive locations for pore opening. Accordingly, untreated aging rats showed a significant overexpression of the active fragment of caspases 3 and 9. IGF-I therapy corrected these parameters of mitochondrial dysfunction and reduced caspase activation. In conclusion, these results show that the cytoprotective effect of IGF-I is closely related to a mitochondrial protection, leading to reduce free radical production, oxidative damage, and apoptosis, and to increased ATP production.

1998 Jan;217(1):53-63.

Oxidative stress and mitochondrial DNA mutations in human aging.

Source

Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.

Abstract

The mitochondrial respiratory system is the major intracellular source of the reactive oxygen species (ROS) and free radicals, which are generated as byproducts during the transfer of electrons from NADH or FADH2 to molecular oxygen under normal physiological conditions. An age-dependent increase in the fraction of these toxic byproducts that may escape the defense mechanism of human and animal cells can induce a broad spectrum of oxidative damage to the biomolecules in the mitochondria and the cell as a whole. Abundant evidence has been gathered to suggest that an elevation of oxidative stress and associated oxidative damages gradually occur in the mitochondria of tissue cells during aging. The mitochondrial DNA (mtDNA), while not protected by histones or DNA-binding proteins, is continually exposed to a high steady-state level of ROS and free radicals in the matrix of the mitochondria. Thus, oxidative modification and mutation of mtDNA occur with great ease, and the extent of such alterations of mtDNA increases exponentially with age. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria elicited by the ever-increasing amount of the ROS further aggravate the mutation and oxidative damage to mtDNA in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits exhibit impaired electron transport function and thereby increase the electron leak and ROS production, which in turn elevate the oxidative stress and oxidative damage to mitochondria. This vicious cycle operates in various tissue cells at different rate and leads to differential accumulation of oxidatively modified and mutant mtDNAs. This may explain the difference in functional decline and structural deterioration of different organs and tissues in human aging. The central role that alterations of the mitochondria and mtDNA may play in aging and age-related degenerative diseases is discussed in relation to the "Mitochondrial theory of aging."