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.

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

“…Finally, investigation of the role of mitochondrial targeted antioxidants or compounds that increase mitochondrial biogenesis and dynamics, such as resveratrol and bezafibrate, firstly in Gcdh‐/‐ mice tissues and cells from patients affected by GA I, may represent in the future novel therapies aiming to reduce reactive species levels and improve cellular respiration in this disease. In this particular, beneficial effects of these compounds have been demonstrated in animal models and fibroblasts from patients with fatty acid oxidation and respiratory chain defects (Bonnefont et al, 2009; Aires et al, 2014; Ørngreen et al, 2014; Djouadi and Bastin, 2019). We expect that this review article may encourage additional investigations in this area.…”

Pyruvate kinase variant of fission yeast tunes carbon metabolism, cell regulation, growth and stress resistance

“…Organisms tune their carbon metabolism to environmental conditions, including stress or available nutrients, which affects fundamental biological processes such as cell proliferation, stress resistance and ageing (New et al , ; Valvezan & Manning, ). Accordingly, aberrant carbon metabolism is the cause of multiple human diseases (Zanella et al , ; Wallace & Fan, ; Djouadi & Bastin, ). Glycolysis converts glucose to pyruvate, which is further processed in alternative pathways; for example, pyruvate can be converted to ethanol (fermentation) or it can be metabolised in mitochondria via the citric acid cycle and oxidative phosphorylation (respiration).…”

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells

“…The use of small molecules aims to improve mitochondrial function, such as respiratory efficiency, ATP production, and reduction of the free radicals, among others. These small molecules are divided into several groups and include antioxidants, cofactors, mitochondrial biogenesis promoting factors, and others [28][29][30][31]. One such molecule is bezafibrate, which is considered as a peroxisome proliferator-activated receptor alpha (PPARα) agonist.…”

“…Some of their target genes are nuclear-encoded respiratory chain (RC) genes, and others are mitochondrial biogenesis and fatty acid oxidation genes. The molecular mechanisms underlying bezafibrate effects on mitochondrial function and biogenesis are partially explained by its ability to upregulate the expression of nuclear-encoded mitochondrial genes [31,32].The main goal of the current study was to examine the effect of bezafibrate on mitochondrial function in fibroblasts derived from a patient carrying a dominant negative DNM1L mutation. Our Cells 2020, 9, 301 3 of 11 findings were corroborated in a fibroblast cell line overexpressing the same mutation.…”