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 our knowledge of the genetic causes is continually expanding, our 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 toward the development of effective therapies.

Keywords: OXPHOS; genetic disease; genomics; mitochondria; mitochondrial disease; respiratory chain.

Figure 1.

Discovery of genes linked to mitochondrial energy generation disorders: mode of identification and link to OXPHOS biogenesis by year (1988–2017*). A, because mtDNA was first linked to human disease in 1988, all 37 genes encoded by the mitochondrial genome have had mutations reported; however, only 35 of these have had adequate levels of evidence reported to confirm pathogenicity (32). The first nuclear gene to be linked to mitochondrial energy generation disorders was identified in 1989 by candidate gene sequencing; an additional 138 genes have been identified by this technique to date (with or without the assistance of linkage or homozygosity studies). Since 2010, MPS technology (including targeted sequencing panels and whole-exome or whole-genome sequencing and RNAseq) has identified 116 additional nuclear genes. Linkage or homozygosity studies have aided in the identification of 119 (or 47%) of the 254 nuclear genes associated with mitochondrial disease. B, in recent years, the number of genes linked to secondary defects in OXPHOS as well as to additional cellular functions has been steadily increasing, most likely due to the relatively unbiased nature of MPS in identifying gene defects. *, numbers are complete up to Nov. 23, 2017.

Figure 2.

Functional categories of genes impacting mitochondrial energy generation. Mutations in genes functioning in a wide variety of pathways have been linked to mitochondrial diseases and can be separated into those with a primary role specific to OXPHOS biogenesis (blue boxes) or those with a secondary impact on OXPHOS that may also involve other cellular functions (orange boxes). These pathways include the following: 1) OXPHOS subunits, assembly factors, and electron carriers; 2) mtDNA maintenance (including dNTP homeostasis); 3) mtDNA expression (including synthesis, processing, and modification of mt-rRNAs, mt-tRNAs, mt-mRNAs, mitoribosome biogenesis, and translation); 4) enzyme cofactors (including Fe-S cluster biogenesis); 5) mitochondrial homeostasis and quality control (including mitochondrial protein import, lipid modification and homeostasis, mitochondrial morphology comprising fission/fusion and cristae organization factors, protein quality control, and apoptosis/autophagy); and 6) general metabolism (e.g. TCA cycle and metabolite transport). CI–CV, OXPHOS complexes I–V; Cyt. c, cytochrome c; CoQ, ubiquinone/coenzyme Q; Δψ, mitochondrial membrane potential; aa, amino acid; OM, outer membrane; IMS, intermembrane space; IM, inner membrane.

Figure 3.

Genes linked to mitochondrial energy generation disorders. This list includes all of the genes reported to date in which mutations have been shown to cause mitochondrial diseases. They are categorized according to whether their role is primarily linked to OXPHOS biogenesis (185 genes of 289) or whether their impact on OXPHOS is secondary, likely involving additional cellular functions (104 genes). Genes listed in red are encoded by mtDNA and in black by nuclear DNA. ^a, genes encoding proteins that either function in the cytosol/nucleus or localize to both the mitochondria and cytosol/nucleus (, , and references therein). ^b, genes encoding dual-function enzymes that affect mitochondrial nucleoside salvage pathways along with their primary function (42, 98, 99). ^c, proteins encoded by TRMT10C and HSD17B10 (MRPP1 and MRPP2) are subunits of the mitochondrial RNase P enzyme, along with MRPP3 encoded by KIAA0391, and are responsible for processing and maturation of mt-tRNAs from polycistronic transcripts. Together, they also form a subcomplex involved in tRNA modification (m¹R9 methylation). HSD17B10 encodes 17β-hydroxysteroid dehydrogenase type 10, a multifunction enzyme that catalyzes the oxidation of a wide variety of fatty acids and steroids, in addition to RNA processing (100). ^d, NUBPL plays a role in the incorporation of Fe-S clusters into OXPHOS complex I (CI) subunits, so it could also be classified as having a role in Fe-S biogenesis (17). ^e, some of the genes within these groups encode proteins that are either cytosolic or recruited from the cytosol to mitochondrial membranes or are reported to have alternative isoforms that are targeted to the mitochondria or cytosol. ^f, although classified as having a role in mitochondrial protein import, AGK and DNAJC19 are also implicated in mitochondrial lipid homeostasis (56, 57, 59). ^g, although classified as a member of the carrier family, SLC25A46 localizes to the mitochondrial outer membrane where it functions in mitochondrial cristae architecture (61).