Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

Mitochondrial DNA (mtDNA) damage is associated with the development of cardiovascular diseases. Cardiac aging plays a central role in cardiovascular diseases. There is accumulating evidence linking cardiac aging to mtDNA damage, including mtDNA mutation and decreased mtDNA copy number. Current wisdom indicates that mtDNA is susceptible to damage by mitochondrial reactive oxygen species (mtROS). This review presents the cellular and molecular mechanisms of cardiac aging, including autophagy, chronic inflammation, mtROS, and mtDNA damage, and the effects of mitochondrial biogenesis and oxidative stress on mtDNA. The importance of nucleoid-associated proteins (Pol γ), nuclear respiratory factors (NRF1 and NRF2), the cGAS-STING pathway, and the mitochondrial biogenesis pathway concerning the development of mtDNA damage during cardiac aging is discussed. Thus, the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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Cold-water immersion following sprint interval training does not alter endurance signaling pathways or training adaptations in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00434.2016 ◽

2017 ◽

Vol 313 (4) ◽

pp. R372-R384 ◽

Cited By ~ 13

Author(s):

James R. Broatch ◽

Aaron Petersen ◽

David J. Bishop

Keyword(s):

Mitochondrial Biogenesis ◽

Molecular Mechanisms ◽

Cold Water ◽

P53 Protein ◽

Water Immersion ◽

Interval Training ◽

Cold Water Immersion ◽

Peroxisome Proliferator ◽

Sprint Interval Training ◽

Single Session

We investigated the underlying molecular mechanisms by which postexercise cold-water immersion (CWI) may alter key markers of mitochondrial biogenesis following both a single session and 6 wk of sprint interval training (SIT). Nineteen men performed a single SIT session, followed by one of two 15-min recovery conditions: cold-water immersion (10°C) or a passive room temperature control (23°C). Sixteen of these participants also completed 6 wk of SIT, each session followed immediately by their designated recovery condition. Four muscle biopsies were obtained in total, three during the single SIT session (preexercise, postrecovery, and 3 h postrecovery) and one 48 h after the last SIT session. After a single SIT session, phosphorylated (p-)AMPK, p-p38 MAPK, p-p53, and peroxisome proliferator-activated receptor-γ coactivator-1α ( PGC-1α) mRNA were all increased ( P < 0.05). Postexercise CWI had no effect on these responses. Consistent with the lack of a response after a single session, regular postexercise CWI had no effect on PGC-1α or p53 protein content. Six weeks of SIT increased peak aerobic power, maximal oxygen consumption, maximal uncoupled respiration (complexes I and II), and 2-km time trial performance ( P < 0.05). However, regular CWI had no effect on changes in these markers, consistent with the lack of response in the markers of mitochondrial biogenesis. Although these observations suggest that CWI is not detrimental to endurance adaptations following 6 wk of SIT, they question whether postexercise CWI is an effective strategy to promote mitochondrial biogenesis and improvements in endurance performance.

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Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters

Frontiers in Physiology ◽

10.3389/fphys.2021.736905 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jonghyuk Park ◽

Jimmy Kim ◽

Toshio Mikami

Keyword(s):

Blood Lactate ◽

Mitochondrial Biogenesis ◽

High Intensity ◽

Lactate Concentration ◽

High Intensity Exercise ◽

Mtdna Copy Number ◽

Single Bout ◽

Extracellular Lactate ◽

Exercise Induced ◽

The Brain

Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.

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Antioxidant and Anti-inflammatory Mechanisms of Astaxanthin in Cardiovascular Diseases

10.20944/preprints202008.0119.v1 ◽

2020 ◽

Author(s):

Carolina Parga Martins Pereira ◽

Ana Carolina Remondi Souza ◽

Andrea Rodrigues Vasconcelos ◽

Pietra Sacramento Prado ◽

José João Name

Keyword(s):

Cardiovascular Diseases ◽

Molecular Mechanisms ◽

Cardiovascular Health ◽

Redox Balance ◽

Cellular Mechanisms ◽

Positive Effects ◽

Antioxidant Agents ◽

Therapeutic Properties ◽

Anti Inflammatory ◽

Preclinical And Clinical Studies

Cardiovascular disease is the most common cause of death. Oxidative stress and inflammation are pathophysiological processes involved in the development of cardiovascular diseases, so anti-inflammatory and antioxidant agents that modulate redox balance have become the targets of research to evaluate their molecular mechanisms and therapeutic properties. Astaxanthin, a carotenoid of the xanthophyll group, has potent antioxidant effects due to its molecular structure and its arrangement in the plasma membrane, factors that favor the neutralization of reactive oxygen and nitrogen species. This carotenoid also stands out for its anti-inflammatory activity, possibly interrelated with its antioxidant effect, as well as for its modulation of lipid and glucose metabolism. Considering the potential positive effects of astaxanthin on cardiovascular health evidenced by preclinical and clinical studies, this paper describes the molecular and cellular mechanisms related to the antioxidant and anti-inflammatory properties of this carotenoid in cardiovascular diseases, especially atherosclerosis.

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Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

10.1101/2021.07.19.452923 ◽

2021 ◽

Author(s):

Caroline Trumpff ◽

Edward Owusu-Ansah ◽

Hans-Ulrich Klein ◽

Annie Lee ◽

Vladislav Petyuk ◽

...

Keyword(s):

Human Brain ◽

Respiratory Chain ◽

Complex I ◽

Molecular Mechanisms ◽

Nuclear Dna ◽

Mitochondrial Protein ◽

Mitochondrial Respiratory Chain ◽

Mtdna Copy Number ◽

Mt Dna ◽

Mitochondrial Respiratory

Mitochondrial respiratory chain (RC) function requires the stochiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

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DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.696428 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sophia Bam ◽

Erin Buchanan ◽

Caitlyn Mahony ◽

Colleen O’Ryan

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Copy Number ◽

Autism Spectrum ◽

Differential Methylation ◽

Mtdna Copy Number ◽

Key Genes

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

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Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function

Aging ◽

10.18632/aging.102647 ◽

2020 ◽

Vol 12 (1) ◽

pp. 650-671 ◽

Cited By ~ 5

Author(s):

Junying Wang ◽

Shaoqi Li ◽

Ju Wang ◽

Feixiang Wu ◽

Yuhan Chen ◽

...

Keyword(s):

Mitochondrial Biogenesis ◽

Cardiac Aging ◽

And Function

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Regulation of TRPV5 and TRPV6 by associated proteins

AJP Renal Physiology ◽

10.1152/ajprenal.00443.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. F1295-F1302 ◽

Cited By ~ 61

Author(s):

Stan F. J. van de Graaf ◽

Joost G. J. Hoenderop ◽

René J. M. Bindels

Keyword(s):

Molecular Mechanisms ◽

Hormonal Control ◽

Trp Channel ◽

Intestinal Lumen ◽

Blood Compartment ◽

Associated Proteins ◽

The Relationship ◽

Insight Into ◽

Prime Target

The epithelial Ca2+ channels TRPV5 and TRPV6 are the most Ca2+-selective members of the TRP channel superfamily. These channels are the prime target for hormonal control of the active Ca2+ flux from the urine space or intestinal lumen to the blood compartment. Insight into their regulation is, therefore, pivotal in our understanding of the (patho)physiology of Ca2+ homeostasis. The recent elucidation of TRPV5/6-associated proteins has provided new insight into the molecular mechanisms underlying the regulation of these channels. In this review, we describe the various means of TRPV5/6 regulation, the role of channel-associated proteins herein, and the relationship between both processes.

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