The Oxidative Phosphorylation System in Mammalian Mitochondria

Papa, Sergio; Martino, Pietro Luca; Capitanio, Giuseppe; Gaballo, Antonio; Rasmo, Domenico De; Signorile, Anna; Petruzzella, Vittoria

doi:10.1007/978-94-007-2869-1_1

Cited by 220 publications

(163 citation statements)

References 286 publications

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“…This order of events is important as it shows that separate regulatory circuits control the production of translational machinery and mtDNA expression and the nuclear components required for oxidative metabolism. This is rather surprising as according to the basic paradigm the assembly of the respiratory chain complexes happens in an orchestrated manner [64], and the unbalance between nuclear and mitochondrially encoded components of the respiratory complexes can result in suboptimal electron transport and ROS generation, as seen in RC assembly deficient models [65,66]. Fittingly, during the upregulation of mitochondrial biogenesis during the first days of postnatal life, cardiomyocytes show simultaneous signs of elevated ROS levels capable of eliciting DNA repair responses [61].…”

Section: Regulation Of Mitochondrial Biogenesis In Heartmentioning

confidence: 99%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

106

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Mitochondria are essential for the development as well as maintenance of the myocardium, the most energy consuming tissue in the human body. Mitochondria are not only a source of ATP energy but also generators of reactive oxygen species (ROS), that cause oxidative damage, but also regulate physiological processes such as the switch from hyperplastic to hypertrophic growth after birth. As excess ROS production and oxidative damage are associated with cardiac pathology, it is not surprising that much of the research focused on the deleterious aspects of free radicals. However, cardiomyocytes are naturally highly adapted against repeating oxidative insults, with evidence suggesting that moderate and acute ROS exposure has beneficial consequences for mitochondrial maintenance and cardiac health. Antioxidant defenses, mitochondrial quality control, mtDNA maintenance mechanisms as well as mitochondrial fusion and fission improve mitochondrial function and cardiomyocyte survival under stress conditions. As these adaptive processes can be induced, promoting mitohormesis or mitochondrial biogenesis using controlled ROS exposure could provide a promising strategy to increase cardiomyocyte survival and prevent pathological remodeling of the myocardium.

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Section: Regulation Of Mitochondrial Biogenesis In Heartmentioning

confidence: 99%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

106

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“…The primary role of mitochondria is the generation of ATP through a complex process of controlled substrate degradation and oxygen consumption known as OxPhos (8,9). Oxidation of nutrient molecules, such as carbohydrates, lipids, and amino acids, yields electrons in the form of reduced hydrogen carriers NADH ϩ and FADH 2 .…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

“…The transfer of electrons along the respiratory chain is accompanied by pumping of protons (H ϩ ) across the inner mitochondrial membrane, which results in transmembrane differences in proton concentration (gradient). The proton-motive force is subsequently used to drive the synthesis of ATP, as H ϩ flows passively back into the matrix through proton pores formed by ATP synthase (1,8,9). Thus, ATP is synthesized by coupling electron transport and H ϩ pumping to phosphorylation of ADP.…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

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Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as a promising target for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol but not cyclosporin A and were nonexistent in mitochondrial DNA-depleted HepG2 cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreased mitochondrial membrane potential, and promoted swelling of valinomycin-treated mitochondria in potassium acetate medium. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy-sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down-regulation of cell cycle, mitochondrial, and oxidative phosphorylation pathway transcripts at 24 h post-treatment. Collectively, our studies demonstrate that the previously reported indirect activation of AMPK and in vitro anticancer properties of SR4 as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity. Hepatocellular carcinoma (HCC)2 is the most common and severe form of liver cancer, accounting for about 80 -90% of primary liver cancers and 5% of all human cancers. More than 600,000 deaths are attributed to HCC every year with 2:1 ratio for men versus women (1, 2). HCC is a primary cancer of hepatocytes that most typically occurs in the setting of known risk factors, including cirrhosis and chronic hepatitis B virus or hepatitis C virus infections (2, 3), although recently, several lines of evidence suggest that type 2 diabetes is also an independent risk factor for HCC development (4). HCC is an aggressive tumor and represents a major health problem as its incidence is increasing. Systemic chemotherapies have proven ineffective against advanced HCC, so it typically leads to death within 6 -20 months (5). Hepatocarcinogenesis is a multistep process involving inflammation, hyperplasia, and dysplasia that finally leads to malignant transformation. In recent years, mitochondria have been found to provide a novel targeting site for new anticancer drugs (known as "mitocans") that ca...

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“…Mitochondria have a variety of important functions in the cell, such as energy production, antiviral innate immune signaling, and regulation of calcium [8][9][10]. Because the human brain needs a plentiful supply of energy to maintain neuronal structure and function, mitochondrial dysfunction (which can cause energy depletion, superoxide overproduction, metabolic imbalance, and disturbed signaling transmission) may be involved in many neurological disorders [11].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Haplogroup A Decreases the Risk of Drug Addiction but Conversely Increases the Risk of HIV-1 Infection in Chinese Addicts

Zhang

Liu

et al. 2015

Mol Neurobiol

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Drug addiction is one of the most serious social problems in the world today and addicts are always at a high risk of acquiring HIV infection. Mitochondrial impairment has been reported in both drug addicts and in HIV patients undergoing treatment. In this study, we aimed to investigate whether mitochondrial DNA (mtDNA) haplogroup could affect the risk of drug addiction and HIV-1 infection in Chinese. We analyzed mtDNA sequence variations of 577 Chinese intravenous drug addicts (289 with HIV-1 infection and 288 without) and compared with 2 control populations (n = 362 and n = 850). We quantified the viral load in HIV-1-infected patients with and without haplogroup A status and investigated the potential effect of haplogroup A defining variants m.4824A > G and m.8794C > T on the cellular reactive oxygen species (ROS) levels by using an allotopic expression assay. mtDNA haplogroup A had a protective effect against drug addiction but appeared to confer an increased risk of HIV infection in addicts. HIV-1-infected addicts with haplogroup A had a trend for a higher viral load, although the mean viral load was similar between carriers of haplogroup A and those with other haplogroup. Hela cells overexpressing allele m.8794 T showed significantly decreased ROS levels as compared to cells with the allele m.8794C (P = 0.03). Our results suggested that mtDNA haplogroup A might protect against drug addiction but increase the risk of HIV-1 infection. The contradictory role of haplogroup A might be caused by an alteration in mitochondrial function due to a particular mtDNA ancestral variant.

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The Oxidative Phosphorylation System in Mammalian Mitochondria

Cited by 220 publications

References 286 publications

The role of mitochondria in cardiac development and protection

The role of mitochondria in cardiac development and protection

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Mitochondrial DNA Haplogroup A Decreases the Risk of Drug Addiction but Conversely Increases the Risk of HIV-1 Infection in Chinese Addicts

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