Mitochondria and aging: A role for the mitochondrial transition pore?

Panel, Mathieu; Ghaleh, Bijan; Morin, Didier

doi:10.1111/acel.12793

Cited by 118 publications

(94 citation statements)

References 214 publications

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“…47 Mitochondria play a vital role in β-oxidation of FFAs, and mitochondrial dysfunctions, such as extensive mitochondrial permeability transition pore (mPTP) opening and impaired respiratory functions, lead to excess ROS production causing apoptotic cell deaths. 48 Das et al have demonstrated that palmitic acid induces mitochondrial fragmentation, calcium overload, and mPTP opening, but melatonin treatment (1 mmol/L for 30 minutes) inhibits these effects in HepG2 cells in vitro. 49 HFD decreased mitochondrial enzyme activities in mice, such as cytochrome C oxidase and pyruvate dehydrogenase, but melatonin administration (10 or 20 mg/kg daily for 4 weeks, i.p.…”

Section: Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress‐induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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Section: Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Sato

Meng

Francis

et al. 2020

Journal of Pineal Research

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“…However, these models have limited application to the aging liver due to differences in their respective molecular and metabolic phenotypes. Since oxidative stress and mitochondrial dysfunction are considered to be critical for senescence and aging [6,11,24,25], we have developed a protocol that produces these changes to induce premature cellular senescence in nontransformed AML12 hepatic cells to study hepatic aging in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Senescent cells also had increased mitochondrial activity compared to control cells. However, this increased activity did not lead to more ATP production due to concomitant increases in basal uncoupling and proton leakage, which are hallmarks of senescent cells [1,25,27,29]. These findings thus explains the reason why there is increased AMP:ATP ratio leading to the AMPK activation often found in senescent cells [1,27,29].…”

Section: Senescent Cells Are Metabolically Hyperactive and Display A mentioning

confidence: 97%

“…Thus, it is critical to verify the fidelity of in vitro models to tissues from aged mice. Although there still remains some uncertainty about the optimal method to induce senescence in vitro; it generally is agreed that oxidative stress and mitochondrial dysfunction play significant roles in the aging process [6,11,24,25]. Accordingly, we have developed a method for inducing hepatic cellular senescence by using mouse hepatic Alpha Mouse Liver 12 (AML12) cells and subjecting them to repetitive oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Singh

Tripathi

Yen

et al. 2020

Preprint

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Although in vitro senescence models have been developed using primary fibroblasts, they may not be applicable for the study of metabolically active organs such as the liver. We thus developed an in vitro protocol to induce senescence in AML12 nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Sequential oxidative stress with hydrogen peroxide induced premature senescence in these cells as they exhibited molecular and metabolic signatures, had increased SA-Gal and H2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled the livers from aged mice.Metabolic phenotyping showed fuel switching towards more glycolysis, mitochondrial glutamine oxidation, and impaired energy production that also was similar to the livers from aged mice. Additionally, Senescence Activated Secretory Proteins (SASPs) sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated an in vitro senescent AML12 cell model that not only show the molecular hallmarks of aging, but also recapitulates the aberrant metabolic phenotype found in aged liver. As such, they represent a novel and useful model to study nutritional, pharmacological, or genetic factors on hepatic metabolism during aging.

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“…mPT induction is closely related to mitochondrial oxidant release; interventions that augment antioxidant defenses and/or decrease the rate of oxidant release are expected to decrease the probability of mPT (reviewed in Kowaltowski et al, 2001;Figueira et al, 2013;Vercesi et al, 2018). Susceptibility to mPT also increases with age in several tissues (Panel et al, 2018). The same is observed with conditions that promote unhealthy aging, such as high-fat diets, obesity and diabetes (Littlejohns et al, 2014;Castillo et al, 2019;Anderson et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Functional Changes Induced by Short Term Caloric Restriction in Cardiac and Skeletal Muscle Mitochondria

Serna

Silva

Kowaltowski

2020

Preprint

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Caloric restriction (CR) is widely known to increase life span and resistance against different types of injuries in several organisms. We have previously shown that mitochondria from livers or brains of CR animals exhibit higher calcium uptake rates and lower sensitivity to calcium-induced mitochondrial permeability transition (mPT), an event related to the resilient phenotype exhibited by these organs. Given the importance of calcium in metabolic control and cell homeostasis, we aimed here to uncover possible changes in mitochondrial calcium handling, redox balance and bioenergetics in cardiac and skeletal muscle mitochondria. Unexpectedly, we found that CR does not alter the susceptibility to mPT in muscle (cardiac or skeletal), nor calcium uptake rates. Despite the lack in changes in calcium transport properties, CR consistently decreased respiration in the presence of ATP synthesis in heart and soleus muscle. In heart, such changes were accompanied by a decrease in respiration in the absence of ATP synthesis, lower maximal respiratory rates and a reduced rate of hydrogen peroxide release. Hydrogen peroxide release was unaltered by CR in skeletal muscle. No changes were observed in inner membrane potentials and respiratory control ratios. Together, these results highlight the tissue-specific bioenergetic and ion transport effects induced by CR, demonstrating that resilience against calcium-induced mPT is not present in all tissues.

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Mitochondria and aging: A role for the mitochondrial transition pore?

Cited by 118 publications

References 214 publications

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Functional Changes Induced by Short Term Caloric Restriction in Cardiac and Skeletal Muscle Mitochondria

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