Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Abstract

Inherited disorders of oxidative phosphorylation cause the clinically and genetically heterogeneous diseases known as mitochondrial energy generation disorders, or mitochondrial diseases. Over the last three decades, mutations causing these disorders have been identified in almost 290 genes, but many patients still remain without a molecular diagnosis. Moreover, while knowledge of the genetic causes is continually expanding, understanding into how these defects lead to cellular dysfunction and organ pathology is still incomplete. Here, we review recent developments in disease gene discovery, functional characterization, and shared pathogenic parameters influencing disease pathology that offer promising avenues towards development of effective therapies.Mitochondrial energy generation disorders (hereafter termed mitochondrial diseases) are a heterogeneous group of rare disorders involving defective oxidative phosphorylation (OXPHOS). The OXPHOS system comprises five enzyme complexes, situated in the mitochondrial inner membrane. The first four complexes and two electron carriers form the respiratory chain, which generates a proton gradient used by complex V (F 1 F o ATP synthase) to generate the majority of cellular ATP. For the purpose of this review, we have focused on genes and mechanisms that have a demonstrated defect in primary energy generation (e.g. components of the OXPHOS system) or a clear expected role in mitochondrial homeostasis and the ability to generate energy (e.g. components of the TCA cycle and pyruvate dehydrogenase complex (PDC) that feed into OXPHOS, or those affecting mitochondrial membranes and structure).

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

“…Recommendations for optimal diagnosis and treatment of this large evolving group are constantly reevaluated…”

“…Some of thiamine and riboflavin defects may also be included in this group given that these vitamins serve as cofactors for oxidative decarboxylation and fatty acid beta‐oxidation, respectively. A large and growing group of already >110 disorders involves the mitochondrial machinery (mitochondrial fusion, fission, replication, mitochondrial protein import and protein quality control, ribosomopathies, mitochondrial DNA depletion and intergenomic modification, mitochondrial tRNA synthetases and tRNA modification, and phospholipid membrane metabolism) . Mitochondrial diseases are clinically diverse and can present at any age.…”

“…A large and growing group of already >110 disorders involves the mitochondrial machinery (mitochondrial fusion, fission, replication, mitochondrial protein import and protein quality control, ribosomopathies, mitochondrial DNA depletion and intergenomic modification, mitochondrial tRNA synthetases and tRNA modification, and phospholipid membrane metabolism). 13 Mitochondrial diseases are clinically diverse and can present at any age. They can manifest in a tissue-specific or multisystemic manner, but most often affect organs with the highest energy demands such as brain, skeletal muscle, eyes and heart.…”

“…About 290 genes registered so far are classified in five general categories according to Frazier et al 13 Recommendations for optimal diagnosis and treatment of this large evolving group are constantly reevaluated. 13…”

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

“…All remaining protein components of the mitochondrial gene maintenance and expression machineries such as proteins responsible for mtDNA transcription, precursor RNA processing enzymes, the mitoribosomal proteins, mitochondrial aminoacyl tRNA synthetases, and others are encoded by the nuclear genes (Hallberg & Larsson, ; Rorbach & Minczuk, ). More than 50 nuclear‐encoded mitochondrial proteins involved in mitochondrial gene expression are linked to heritable disorders (Frazier, Thorburn, & Compton, ; Powell, Nicholls, & Minczuk, ; Rahman & Rahman, ; Stenton & Prokisch, ; Van Haute et al, ).…”