Mild pentachlorophenol-mediated uncoupling of mitochondria depletes ATP but does not cause an oxidized redox state or dopaminergic neurodegeneration in .

Aims: Mitochondrial dysfunction is implicated in several diseases, including neurological disorders such as Parkinson's disease. However, there is uncertainty about which of the many mechanisms by which mitochondrial function can be disrupted may lead to neurodegeneration. Pentachlorophenol (PCP) is an organic pollutant reported to cause mitochondrial dysfunction including oxidative stress and mitochondrial uncoupling.

Resistance of mitochondrial DNA to cadmium and Aflatoxin B1 damage-induced germline mutation accumulation in C. elegans.

Mitochondrial DNA (mtDNA) is prone to mutation in aging and over evolutionary time, yet the processes that regulate the accumulation of de novo mtDNA mutations and modulate mtDNA heteroplasmy are not fully elucidated. Mitochondria lack certain DNA repair processes, which could contribute to polymerase error-induced mutations and increase susceptibility to chemical-induced mtDNA mutagenesis. We conducted error-corrected, ultra-sensitive Duplex Sequencing to investigate the effects of two known nuclear genome mutagens, cadmium and Aflatoxin B1, on germline mtDNA mutagenesis in Caenorhabditis elegans.

Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans.

The consequences of damage to the mitochondrial genome (mtDNA) are poorly understood, although mtDNA is more susceptible to damage resulting from some genotoxicants than nuclear DNA (nucDNA), and many environmental toxicants target the mitochondria. Reports from the toxicological literature suggest that exposure to early-life mitochondrial damage could lead to deleterious consequences later in life (the "Developmental Origins of Health and Disease" paradigm), but reports from other fields often report beneficial ("mitohormetic") responses to such damage. Here, we tested the effects of low (causing no change in lifespan) levels of ultraviolet C (UVC)-induced, irreparable mtDNA damage during early development in Caenorhabditis elegans.

Ablation of in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload.

Mitochondrial Sirtuin 5 (SIRT5) is an NAD-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function and metabolism under stress. Previously, we described a phenotype of increased mortality in whole-body SIRT5KO mice exposed to chronic pressure overload compared with their littermate WT controls.

Sirtuin 5 is required for mouse survival in response to cardiac pressure overload.

In mitochondria, the sirtuin SIRT5 is an NAD-dependent protein deacylase that controls several metabolic pathways. Although a wide range of SIRT5 targets have been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains unclear. Given that SIRT5 expression is highest in the heart and that sirtuins are commonly stress-response proteins, we used an established model of pressure overload-induced heart muscle hypertrophy caused by transverse aortic constriction (TAC) to determine SIRT5's role in cardiac stress responses.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model.

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3).

Role of NAD and mitochondrial sirtuins in cardiac and renal diseases.

The coenzyme nicotinamide adenine dinucleotide (NAD) has key roles in the regulation of redox status and energy metabolism. NAD depletion is emerging as a major contributor to the pathogenesis of cardiac and renal diseases and NAD repletion strategies have shown therapeutic potential as a means to restore healthy metabolism and physiological function. The pleotropic roles of NAD enable several possible avenues by which repletion of this coenzyme could have therapeutic efficacy.

Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.

The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared.

Targeting sirtuins for the treatment of diabetes.

Sirtuins are a class of NAD-dependent deacetylases, such as deacetylases, that have a wide array of biological functions. Recent studies have suggested that reduced sirtuin action is correlated with Type 2 diabetes. Both overnutrition and aging, which are two major risk factors for diabetes, lead to decreased sirtuin function and result in abnormal glucose and lipid metabolism.