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Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies

Abstract : Mitochondrial fatty acid oxidation (FAO) and respiratory chain (RC) defects form a large group of inherited monogenic disorders sharing many common clinical and pathophysiological features, including disruption of mitochondrial bioenergetics, but also, for example, oxidative stress and accumulation of noxious metabolites. Interestingly, several transcription factors or co-activators exert transcriptional control on both FAO and RC genes, and can be activated by small molecules, opening to possibly common therapeutic approaches for FAO and RC deficiencies. Here, we review recent data on the potential of various drugs or small molecules targeting pivotal metabolic regulators: peroxisome proliferator activated receptors (PPARs), sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and protein kinase A (PKA)) or interacting with reactive oxygen species (ROS) signaling, to alleviate or to correct inborn FAO or RC deficiencies in cellular or animal models. The possible molecular mechanisms involved, in particular the contribution of mitochondrial biogenesis, are discussed. Applications of these pharmacological approaches as a function of genotype/phenotype are also addressed, which clearly orient toward personalized therapy. Finally, we propose that beyond the identification of individual candidate drugs/molecules, future pharmacological approaches should consider their combination, which could produce additive or synergistic effects that may further enhance their therapeutic potential. The inborn defects of mitochondrial fatty acid β-oxidation (FAO) and respiratory chain (RC) rank among the most frequent genetic disorders of energy metabolism in human [1]. Although both groups of diseases are often presented and discussed separately by clinicians and researchers, they share many common features. Among them: (i) both groups of disorders are caused by the partial or total loss of function of a single protein or enzyme essential to the mitochondrial RC or to the FAO pathway; (ii) a large number of disease-causing genes have been identified, and each individual disorder is generally associated with a wide panel of gene mutations, with poorly understood genotype-phenotype correlations; (iii) the pathogenesis of these diseases involves not only bioenergetics defects due to disruption of mitochondrial structure and function, but also multiple other mechanisms-including ROS overproduction, oxidative stress, and accumulation of noxious intermediates; (iv) these disorders are clinically heterogeneous and can manifest in neonates, children, or adults with very diverse symptoms affecting one or several organs with high energy demand-including heart, skeletal muscle, liver, and brain; and (v) most of these disorders remain without treatment to date. Most importantly, and as we will see in this review, the FAO pathway and mitochondrial RC can be regulated, directly or indirectly, by the same transcription factors or co-activators, which leads to eventually propose the
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Fatima Djouadi, Jean Bastin. Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies. Cells, MDPI, 2019, 8 (4), pp.289. ⟨10.3390/cells8040289⟩. ⟨inserm-02893959⟩

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