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Mitochondrial Pathologies and Their Neuromuscular Manifestations
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Carlos Ortez, Andrés Nascimento
Myopathy and exercise intolerance with defect of complex I assembly was described with ACAD9, which is, to date the first nuclear gene involved in isolated muscular phenotype with complex I deficiency71. Exercise intolerance appears in childhood combined with hyperlactatemia, strong nauseas and mental slowing after exercise, and improvement by high doses of riboflavin.
Current biochemical treatments of mitochondrial respiratory chain disorders
Published in Expert Opinion on Orphan Drugs, 2019
Robert Heaton, Lauren Millichap, Fatima Saleem, Jennifer Gannon, Gemma Begum, Iain P. Hargreaves
Riboflavin or vitamin B2 acts as a precursor of FMN (Flavin mononucleotide) and FAD (flavin adenine dinucleotide) which are prosthetic groups for MRC complex I and II, respectively [33]. Riboflavin obtained from the diet enters the mitochondria from the cytosol by means of specific transporters and is then converted into either FMN and FAD [33]. Therefore, riboflavin transporters are essential for the maintenance of mitochondrial riboflavin homeostasis which if impaired can result in MRC dysfunction with a consequent impairment of oxidative phosphorylation [33]. This is illustrated in cases of Brown Vialetto Van Laere disease which is associated with riboflavin transporter detects and a concomitant impairment in the activities MRC complex I and II in patient fibroblasts (skin cells) [34]. Patients with this riboflavin transporter defect have been reported to show clinical improvement following high dose riboflavin therapy [35]. Furthermore, patients with mutations in the ACAD9, the FADH2 dependent MRC complex I assembly factor have also been reported to show clinical improvement following treatment with riboflavin [36]. Commensurate with this clinical improve, an increased in MRC complex I activity was also reported in fibroblasts from patients with this condition following supplementation with riboflavin [37]. It has been suggested that the increase in the intra-mitochondrial FAD concentration following riboflavin supplementation may improve the folding capacity of mutant flavoprotein assembly factors [36].
Liver Pathology in Mitochondrial Complex I Deficiency from Bi-Allelic Mutations in NDUFS2: A Report of Findings at Autopsy
Published in Fetal and Pediatric Pathology, 2020
Ashlie Rubrecht, William Clapp, Archana Shenoy
Hepatocellular cytoplasmic eosinophilia and microvesicular steatosis are well documented features of mitochondriopathy [3,5] and have also been demonstrated previously in a postmortem report of ACAD9 mutation associated mitochondrial complex I deficiency [1]. However, as demonstrated in Hazard et al.’s review of three cases of mitochondrial DNA depletion syndrome with different mutations and our case, these histologic findings may be seen across the spectrum of mitochondrial disorders and do not appear to be specific to any sub-group or mutation profile.
Putative adjunct therapies to target mitochondrial dysfunction and oxidative stress in phenylketonuria, lysosomal storage disorders and peroxisomal disorders
Published in Expert Opinion on Orphan Drugs, 2020
Nadia Turton, Tricia Rutherford, Dick Thijssen, Iain P Hargreaves
Dietary vitamin B2 and B3 both play essential roles in the maintenance of mitochondrial functioning. B2 or riboflavin is a precursor of Flavin mononucleotide (FMN) and Flavin adenine dinucleotide (FAD) which are prosthetic groups of ETC complexes I and II, respectively [93]. Vitamin B3 however, encompasses nictonic acid, nicotinamide, and nicotinamide riboside (NR), which are precursors of the coenzyme NAD+, and its reduced form NADH [94]. NADH donates two electrons to ETC complex I (see Figure 4). A disturbance of B2 metabolism as well as poor absorption has resulted in inadequate cellular levels of FMN and FAD, resulting in mitochondrial dysfunction and riboflavin associated neurodegenerative disorders [93]. When B2 is supplemented or consumed via the diet, it requires specific transporters to convey it from the cytosol into the mitochondria [93]. Interestingly, defects in these riboflavin transporters, for example, in brown Vialetto Van Laere disease (disease associated with a Loss-of-function mutations in two riboflavin transporter genes, SLC52A2, and SLC52A3), have been associated with a loss of ETC complex I and II activities in fibroblasts of patients with SLC52A2 mutations [95]. However, Gerards et al [96] reported that in complex I deficient patients (mutations in the ACAD9 gene), complex I activity was increased from 17% to 47% following treatment with 300 mg/day riboflavin [96]. It is likely that treatment with riboflavin is able to increase the intra-mitochondrial FAD concentration which compensates for the reduction in the folding capacity of the mutant complex I flavoprotein prosthetic group [97]. Riboflavin has also been demonstrated to promote the assembly of ETC complexes I and IV into the super-complex with complex III, thus enhancing the super-complex formation of the ETC [98]. Therefore, riboflavin treatment may enhance the observed defects in ETC function in IEM in view of its role as a prosthetic group for complexes I and II, as well as its ability to enhance super-complex assembly.