Evaluation of the Mitochondrial Respiratory Chain and Oxidative Phosphorylation System Using Yeast Models of OXPHOS Deficiencies (original) (raw)
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Mitochondrial diseases Part III: Therapeutic interventions in mouse models of oxphos deficiencies
Mitochondrion, 2015
Mitochondrial defects are the cause of numerous disorders affecting the oxidative phosphorylation system (OXPHOS) in humans leading predominantly to neurological and muscular degeneration. The molecular origin, manifestations, and progression of mitochondrial diseases have a broad spectrum, which makes very challenging to find a globally effective therapy. The study of the molecular mechanisms underlying the mitochondrial dysfunction indicates that there is a wide range of pathways, enzymes and molecules that could be potentially targeted for therapeutic purpose. Therefore, focusing on the pathology of the disease is essential to design new treatments. In this review, we will summarize and discuss the different therapeutic interventions tested in some mouse models of mitochondrial diseases laying emphasis on the molecular mechanisms of action and their potential applications.
Mitochondrion, 2015
Mitochondrial disorders are defined as defects that affect the oxidative phosphorylation system (OXPHOS). They are characterized by a heterogeneous array of clinical presentations due in part to a wide variety of factors required for proper function of the components of the OXPHOS system. There is no cure for these disorders owing our poor knowledge of the pathogenic mechanisms of disease. To understand the mechanisms of human disease numerous mouse models have been developed in recent years. Here we summarize the features of several mouse models of mitochondrial diseases directly related to those factors affecting mtDNA maintenance, replication, transcription, translation as well to other proteins that are involved in mitochondrial dynamics and quality control which affect mitochondrial OXPHOS function without been intrinsic components of the system. We discuss how these models have contributed to our understanding of mitochondrial diseases and their pathogenic mechanisms.
Mitochondrion, 2015
Mitochondrial disorders are the most common inborn errors of metabolism affecting the oxidative phosphorylation system (OXPHOS). Because of the poor knowledge of the pathogenic mechanisms, a cure for these disorders is still unavailable and all the treatments currently in use are supportive more than curative. Therefore, in the past decade a great variety of mouse models have been developed to assess the in vivo function of several mitochondrial proteins involved in human diseases. Due to the genetic and physiological similarity to humans, mice represent reliable models to study the pathogenic mechanisms of mitochondrial disorders and are precious to test new therapeutic approaches. Here we summarize the features of several mouse models of mitochondrial diseases directly related to defects in subunits of the OXPHOS complexes or in assembly factors. We discuss how these models recapitulate many human conditions and how they have contributed to the understanding of mitochondrial function in health and disease.
Control of OXPHOS efficiency by complex I in brain mitochondria
Neurobiology of Aging, 2009
In the present work we have analysed the efficiency (P/O ratio) of energy production by oxidative phosphorylation (OXPHOS) in rat brain, liver and heart mitochondria. This study has revealed tissue-specific differences in the mean values of P/O ratios and ATP production rates. A marked dependence of the P/O ratio on the respiration rates has been observed with complex I (NADH:ubiquinone oxidoreductase), but not with complex II (succinate dehydrogenase) respiratory substrates. The physiological impact of the P/O variations with complex I substrates has been further confirmed by extending the analysis to brain mitochondria from three independent groups of animals utilized to study the effects of dietary treatments on the age-related changes of OXPHOS. The general site-specificity of the rate-dependent P/O variability indicates that the decoupling, i.e. decreased coupling between electron transfer and proton pumping, is likely to be mostly due to slip of mitochondrial complex I. These findings suggest an additional mechanism for the pivotal role played by the energy-conserving respiratory complex I in the physiological and adaptive plasticity of mitochondrial OXPHOS.
Journal of Bioenergetics and Biomembranes, 2008
Thirty years after Peter Mitchell was awarded the Nobel Prize for the chemiosmotic hypothesis, which links the mitochondrial membrane potential generated by the proton pumps of the electron transport chain to ATP production by ATP synthase, the molecular players involved once again attract attention. This is so because medical research increasingly recognizes mitochondrial dysfunction as a major factor in the pathology of numerous human diseases, including diabetes, cancer, neurodegenerative diseases, and ischemia reperfusion injury. We propose a model linking mitochondrial oxidative phosphorylation (OxPhos) to human disease, through a lack of energy, excessive free radical production, or a combination of both. We discuss the regulation of OxPhos by cell signaling pathways as a main regulatory mechanism in higher organisms, which in turn determines the magnitude of the mitochondrial membrane potential: if too low, ATP production cannot meet demand, and if too high, free radicals are produced. This model is presented in light of the recently emerging understanding of mechanisms that regulate mammalian cytochrome c oxidase and its substrate cytochrome c as representative enzymes for the entire OxPhos system.
Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases
Biochemical Journal, 2000
Metabolic control analysis has often been used for quantitative studies of the regulation of mitochondrial oxidative phosphorylations (OXPHOS). The main contribution of this work has been to show that the control of mitochondrial metabolic fluxes can be shared among several steps of the oxidative phosphorylation process, and that this distribution can vary according to the steady state and the tissue. However, these studies do not show whether this observed variation in the OXPHOS control is due to the experimental conditions or to the nature of the mitochondria. To find out if there actually exists a tissue variation in the distribution of OXPHOS control coefficients, we determined the control coefficients of seven OXPHOS complexes on the oxygen-consumption flux in rat mitochondria isolated from five different tissues under identical experimental conditions. Thus in
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2009
Defects in the oxidative phosphorylation system (OXPHOS) are responsible for a group of extremely heterogeneous and pleiotropic pathologies commonly known as mitochondrial diseases. Although many mutations have been found to be responsible for OXPHOS defects, their pathogenetic mechanisms are still poorly understood. An important contribution to investigate the in vivo function of several mitochondrial proteins and their role in mitochondrial dysfunction, has been provided by mouse models. Thanks to their genetic and physiologic similarity to humans, mouse models represent a powerful tool to investigate the impact of pathological mutations on metabolic pathways. In this review we discuss the main mouse models of mitochondrial disease developed, focusing on the ones that directly affect the OXPHOS system. j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a m c r