Mitochondrial diseases in adults

Abstract

Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype–phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy‐dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.

Mitochondrial DNA copy number in human disease: the more the better?

“…Besides being the direct cause of primary mitochondrial diseases, typically characterised by severe mitochondrial impairment in multiple tissues (Tuppen et al, 2010), mtDNA mutations have also been implicated in the pathophysiology of common age-associated human diseases (Reeve et al, 2008;Tuppen et al, 2010;Greaves et al, 2012;La Morgia et al, 2020;Rahman, 2020) and in the naturally occurring ageing process (Larsson, 2010). It is well established that point mutations in tRNA genes or single large deletions of mtDNA lead to functional impairment or lack of one or several tRNAs.…”

“…These disorders can affect different cell types and organs, and can therefore, cause a wide range of symptoms. Mitochondrial diseases have been classified according to their clinical manifestations and can be caused either by mutations in nuclear genes, leading to reduced mtDNA expression, or by primary mtDNA mutations directly impairing the function or abundance of mtDNA-encoded gene products (Rahman, 2020;La Morgia et al, 2020). mtDNA depletion syndromes (MDS) (Viscomi & Zeviani, 2017) are autosomal recessive disorders characterized by a strong tissue-specific reduction of mtDNA levels due to mutations in genes involved in various mtDNA maintenance processes, ranging from mitochondrial nucleotide metabolism, mtDNA replication, mitochondrial dynamics and quality control (Table 1).…”

“…These disorders can affect different cell types and organs, and can therefore cause a wide range of symptoms. Mitochondrial diseases have been classified according to their clinical manifestations and can be caused either by mutations in nuclear genes, leading to reduced mtDNA expression, or by primary mtDNA mutations directly impairing the function or abundance of mtDNA-encoded gene products [59,60].…”

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

“…Genetic defects affecting these respiratory complexes often lead to dysfunctional ΔΨm with significant consequences to the viability of the cells. However, a comprehensive description of clinical features and genetic causes of PMD is beyond the scope of this manuscript; please refer to [ 20 , 21 ] for an exhaustive list.…”

Mitochondria in human disease

“…The clinical phenotypes in adults with mitochondrial diseases are summarized by Valerio Carelli and colleagues [5] with a particular focus on mtDNA mutations and nuclear mutations impairing mtDNA maintenance or replication. The genotype – clinical phenotype correlations remain poorly understood in adults with mitochondrial disease.…”