Abstract
Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.
Highlights
MtDNA mutations could affect any gene encoding the 13 core subunits of the mitochondrial respiratory chain (MRC) complexes, the 22 mitochondrial tRNAs, or the two rRNAs
Mutations in the same gene can lead to different clinical presentation; for instance, mitochondrial phenotypes described in patients with MT-ATP6 mutations span from maternally inherited Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)[9], to Charcot–Marie–Tooth disease [10], late-onset hereditary spastic paraplegia-like disorder [11], and myoclonic epilepsy with ragged red fibers (MERRF)-like phenotype [12]
A further, widely accepted, genetic classification of Primary mitochondrial diseases (PMD) is based on the function of the protein products encoded by the mutated genes and includes (i) structural subunits of complexes I-IV, and ATP synthase complex F0F1; (ii) assembly factors of complexes I-IV, and ATP synthase complex F0F1; (iii) factors performing or regulating replication, expression, and stability of mitochondrial DNA (mtDNA); (iv) proteins related to mitochondrial biogenesis or indirectly associated to oxidative phosphorylation (OXPHOS); (v) proteins of the execution pathways, such as fission/fusion and apoptosis; (vi) proteins involved in the biosynthesis and metabolism of cofactors; or (vii) proteins involved in the biosynthesis and metabolism of mitochondrial membrane lipids
Summary
Primary mitochondrial disorders (PMD) are a group of rare diseases affecting approximately 1 in 4300 live birth and causing progressive, incurable defects often resulting in premature death. PMD are characterized by a high genetic, biochemical, and clinical complexity that arise from the dysfunction of the oxidative phosphorylation (OXPHOS), the essential, final pathway for aerobic metabolism [1] Such impairment is caused by mutations in genes encoding for proteins involved in mitochondrial respiratory chain (MRC) biogenesis, (i.e., subunits of MRC complexes, assembly factors, or post-assembly quality controllers), or by mutations in genes involved in other mitochondrial functions, including fission and fusion machinery, mitochondrial DNA (mtDNA) maintenance, heme biosynthesis, and iron/sulfur metabolism, among others [2]. The mitochondrial membrane potential (∆Ψm) generated by proton-pumping Complexes I, III, and IV, is essential for the energy storage and for the elimination of disabled mitochondria [19] Genetic defects affecting these respiratory complexes often lead to dysfunctional ∆Ψm with significant consequences to the viability of the cells. We will review the most substantial advances in the treatment of PMD and discuss future therapeutic perspectives
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