Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases

Wan, Wei; Hua, Fuzhou; Pu, Fang; Li, Chang; Deng, Fang; Chen, Shoulin; Ying, Jun; Wang, Xifeng

doi:10.3389/fnagi.2022.845330

Cited by 25 publications

(10 citation statements)

References 153 publications

(190 reference statements)

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“…Despite unaltered PARGC1 expression, we observed reduced expression of key transcription factors, NRF1 that regulates expression of nuclear DNA‐encoded mitochondrial genes and TFAM that reguates expression of mitochondrial DNA‐encoded mitochondrial genes. SIRT1 and mTOR have ability to activate PGC‐1α, 23,24 regulate mitophagy and UPRmt 25–28 and we showed that they were downregulated in both ICM and DCM. Collectively, these data suggest reduced mitochondrial biogenesis in failing human hearts.…”

Section: Discussionmentioning

confidence: 68%

Heart failure in patients is associated with downregulation of mitochondrial quality control genes

Svaguša

Sikiric

Milavic

et al. 2023

Eur J Clin Investigation

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BackgroundMitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure.MethodsMyocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real‐time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion‐fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry.ResultsThe following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT‐ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM.ConclusionsHeart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion‐fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.

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Section: Discussionmentioning

confidence: 68%

Heart failure in patients is associated with downregulation of mitochondrial quality control genes

Svaguša

Sikiric

Milavic

et al. 2023

Eur J Clin Investigation

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“…In addition, insulin signaling [82] and AMPK signaling [83,84] pathways that are implicated in mitophagy activation are upregulated in old HCR rats. Further supporting impaired mitophagy in old LCR rats, mitochondrial quality control and biogenesis effectors SIRT1/TFAM are downregulated in aged LCR rats [85] , whereas SIRT3 levels in SIRT3/FOXO3A-PINK1-PARKIN axis [86] linked to higher mitophagy are high in HCR rats [87] .…”

Section: Discussionmentioning

confidence: 87%

Mitochondrial DAMPs-dependent inflammasome activation during aging induces vascular smooth muscle cell dysfunction and aortic stiffness in low aerobic capacity rats

Canugovi¹,

Stevenson²,

Vendrov³

et al. 2022

J Cardiovasc Aging

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Introduction: Low aerobic exercise capacity is an independent risk factor for cardiovascular disease (CVD) and a predictor of premature death. In combination with aging, low aerobic capacity lowers the threshold for CVD. Aim: Since low aerobic capacity and aging have been linked to mitochondrial oxidative stress and dysfunction, we investigated whether aged Low-Capacity Runner (LCR) rats (27 months) had vascular dysfunction compared to High-Capacity Runner (HCR) rats. Methods and Results: A significant decrease in aortic eNOS levels and vasodilation as well as an increase in aortic collagen and stiffness were observed in aged LCR rats compared to age and sex-matched HCR rats. There was a correlation between age-related vascular dysfunction and increased levels of ROS and DNA damage in aortas of LCR rats. Moreover, mitochondrial oxygen consumption, membrane potential, ATP levels, and mitophagy were lower in VSMCs of aged LCR rats. VSMCs from older LCR rats showed AIM2 inflammasome activation. VSMCs of young (4 months old) LCR rats treated with purified mitochondrial damage-associated molecular patterns (DAMP) recapitulated an inflammasome activation phenotype similar to that seen in aged rat VSMCs. Rapamycin, a potent immunosuppressant, induced mitophagy, stimulated electron transport chain activity, reduced inflammasome activity, mitochondrial ROS and DAMP levels in VSMCs from aged LCR rats. MitoTEMPO, a mitochondrial ROS scavenger, was similarly effective on VSMCs from aged rats. Conclusion: The findings suggest that impaired mitophagy and inflammasome activation in the vasculature under conditions of low aerobic exercise capacity during aging results in arterial dysfunction and aortic stiffness. In older adults with reduced aerobic capacity, mitochondrial antioxidants, mitophagy induction, and inflammasome inhibition may be effective therapeutic strategies for enhancing vascular health.

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“…Since mitochondria supply energy and epigenomic substrates to the nucleus and interact with it closely via mitohormetic and mitonuclear balance systems [ 148 , 149 ] metabolic inhibition implies epigenomic disruption. Mitochondrial inhibition is well established as one of the key hallmarks of aging [ 1 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 ] and implicated pathophysiological pathways include such novel mechanisms as the leakage of mitochondrial DNA into the cytosol and stimulation of innate γ-interferon-dependent immunity via the cGAS-STING pathway [ 156 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

Reece

Hulse

2022

IJERPH

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Background: Twelve separate streams of empirical data make a strong case for cannabis-induced accelerated aging including hormonal, mitochondriopathic, cardiovascular, hepatotoxic, immunological, genotoxic, epigenotoxic, disruption of chromosomal physiology, congenital anomalies, cancers including inheritable tumorigenesis, telomerase inhibition and elevated mortality. Methods: Results from a recently published longitudinal epigenomic screen were analyzed with regard to the results of recent large epidemiological studies of the causal impacts of cannabis. We also integrate theoretical syntheses with prior studies into these combined epigenomic and epidemiological results. Results: Cannabis dependence not only recapitulates many of the key features of aging, but is characterized by both age-defining and age-generating illnesses including immunomodulation, hepatic inflammation, many psychiatric syndromes with a neuroinflammatory basis, genotoxicity and epigenotoxicity. DNA breaks, chromosomal breakage-fusion-bridge morphologies and likely cycles, and altered intergenerational DNA methylation and disruption of both the histone and tubulin codes in the context of increased clinical congenital anomalies, cancers and heritable tumors imply widespread disruption of the genome and epigenome. Modern epigenomic clocks indicate that, in cannabis-dependent patients, cannabis advances cellular DNA methylation age by 25–30% at age 30 years. Data have implications not only for somatic but also stem cell and germ line tissues including post-fertilization zygotes. This effect is likely increases with the square of chronological age. Conclusion: Recent epigenomic studies of cannabis exposure provide many explanations for the broad spectrum of cannabis-related teratogenicity and carcinogenicity and appear to account for many epidemiologically observed findings. Further research is indicated on the role of cannabinoids in the aging process both developmentally and longitudinally, from stem cell to germ cell to blastocystoids to embryoid bodies and beyond.

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Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases

Cited by 25 publications

References 153 publications

Heart failure in patients is associated with downregulation of mitochondrial quality control genes

Heart failure in patients is associated with downregulation of mitochondrial quality control genes

Mitochondrial DAMPs-dependent inflammasome activation during aging induces vascular smooth muscle cell dysfunction and aortic stiffness in low aerobic capacity rats

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

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