Strategies for fighting mitochondrial diseases

Viscomi, Carlo; Zeviani, Massimo

doi:10.1111/joim.13046

Cited by 48 publications

(44 citation statements)

References 120 publications

(131 reference statements)

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“…Strategies with potential general applicability to several, if not all, mitochondrial diseases have been proposed over the past 10 years by us and others. 1 These include approaches aimed at (1) increasing mitochondrial biogenesis; (2) clearing dysfunctional organelles by stimulating mitophagy; and, although more controversial, (3) by-passing the mitochondrial respiratory chain (MRC) complex defects by using alternative oxidases or (4) reversing the mitochondrial unfolded stress response. An additional promising approach is based on the moderate overexpression of Opa1 , which encodes a master regulator of shape and function of mitochondrial cristae.…”

Section: Introductionmentioning

confidence: 99%

Opa1 Overexpression Protects from Early-Onset Mpv17−/−-Related Mouse Kidney Disease

et al. 2020

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Moderate overexpression of Opa1 , the master regulator of mitochondrial cristae morphology, significantly improved mitochondrial damage induced by drugs, surgical denervation, or oxidative phosphorylation (OXPHOS) defects due to specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of this approach in the Mpv17 −/− mouse, characterized by profound, multisystem mitochondrial DNA (mtDNA) depletion. After the crossing with Opa1 tg mice, we found a surprising anticipation of the severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17 − / − animals as a late-onset clinical feature (after 12–18 months of life). In contrast, Mpv17 −/− animals from this new “mixed” strain died at 8 – 9 weeks after birth because of severe kidney failure However, Mpv17 − / − ::Opa1 tg mice lived much longer than Mpv17 − / − littermates and developed the kidney dysfunction much later. mtDNA content and OXPHOS activities were significantly higher in Mpv17 − / − ::Opa1 tg than in Mpv17 − / − kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17 − / − ::Opa1 tg versus Mpv17 − / − kidney and isolated podocytes. Mechanistically, the protective effect of Opa1 overexpression in this model was mediated by a block in apoptosis due to the stabilization of the mitochondrial cristae. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be effective against mtDNA depletion syndromes.

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Section: Introductionmentioning

confidence: 99%

Opa1 Overexpression Protects from Early-Onset Mpv17−/−-Related Mouse Kidney Disease

et al. 2020

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“…In the past decades, remarkable advances have been made in defining the molecular and genetic basis of different types of mitochondrial diseases, including those associated with MCs. Progress has been achieved despite the fact that many mitochondrial diseases are extremely heterogeneous clinically, biochemically, and genetically, and many of them are multi-system disorders affecting several organs [5]. As shown in this review, the number and understanding of the diseases associated with MCs is rapidly growing, and the connections between the mutations, defective transport, altered metabolism, and pathogenic mechanisms underlying the symptoms start to be better comprehended.…”

Section: Discussionmentioning

confidence: 97%

“…Several complementary approaches, which include methods of general and personalized precision medicine, may be applied for efficient treatment. General approaches to improve and facilitate mitochondrial function utilize compounds such as antioxidants, factors that stimulate mitochondrial biogenesis (through signaling pathways and transcription factors), or clearance of defective mitochondria by autophagy and lysosomal removal [2,5]. For some of the MC-associated diseases, appropriate diets often supplemented with specific metabolites or cofactors are being used or are undergoing clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…These defects give rise to, for example, Leigh syndrome, LHON (Leber hereditary optic neuropathy), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome), MERRF (myoclonic epilepsy with ragged fibers), and NARP (neurogenic muscle weakness ataxia and retinitis pigmentosa) [3,4]. The pathogenic nuclear mutations affect mitochondrial proteins involved in many important processes, such as the respiratory chain, oxidative phosphorylation, metabolism, cofactor biosynthesis, transport, replication, transcription, translation, iron homeostasis, cell signalling, organelle dynamics, protein biogenesis, and complex assembly [5]. Among the mitochondrial diseases caused by mutations in nuclear genes are: Friedreich's ataxia, dominant optic atrophy, Barth syndrome, Rett syndrome, spastic paraplegia, coenzyme Q10 deficiency, and progressive external ophthalmoplegia [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

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In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.

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“…heart failure, diabetes and epilepsy. This scenario is now rapidly changing and the review article by Carlo Viscomi and Massimo Zeviani [9] lists a number of treatment strategies. Both general approaches, e.g.…”

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confidence: 99%