Human diseases associated with defects in assembly of OXPHOS complexes

Abstract

The structural biogenesis and functional proficiency of the multiheteromeric complexes forming the mitochondrial oxidative phosphorylation system (OXPHOS) require the concerted action of a number of chaperones and other assembly factors, most of which are specific for each complex. Mutations in a large number of these assembly factors are responsible for mitochondrial disorders, in most cases of infantile onset, typically characterized by biochemical defects of single specific complexes. In fact, pathogenic mutations in complex-specific assembly factors outnumber, in many cases, the repertoire of mutations found in structural subunits of specific complexes. The identification of patients with specific defects in assembly factors has provided an important contribution to the nosological characterization of mitochondrial disorders, and has also been a crucial means to identify a huge number of these proteins in humans, which play an essential role in mitochondrial bioenergetics. The wide use of next generation sequencing (NGS) has led to and will allow the identifcation of additional components of the assembly machinery of individual complexes, mutations of which are responsible for human disorders. The functional studies on patients’ specimens, together with the creation and characterization of in vivo models, are fundamental to better understand the mechanisms of each of them. A new chapter in this field will be, in the near future, the discovery of mechanisms and actions underlying the formation of supercomplexes, molecular structures formed by the physical, and possibly functional, interaction of some of the individual respiratory complexes, particularly complex I (CI), III (CIII), and IV (CIV).

MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

“…Many of these assembly factors have been linked to severe human disorders mostly affecting high-energy-demanding organs, such as heart, liver, muscle, or brain [11,12]. Many of these assembly factors have been linked to severe human disorders mostly affecting high-energy-demanding organs, such as heart, liver, muscle, or brain [11,12].…”

Thyroid Stimulating Hormone Triggers Hepatic Mitochondrial Stress through Cyclophilin D Acetylation

“…The first four complexes including CytC oxidase (COX), together with CytC, are the main components of the mitochondrial respiratory chain. Assembly factors of OXPHOS have been reported in the literature as responsible for many mitochondrial diseases in humans [47]. We used COX IV as an internal control of mitochondrial protein and tested the release of CytC to check the extent of respiratory chain injury (Figure 3(c)).…”

Chlamydomonas reinhardtii as a plant model system to study mitochondrial complex I dysfunction

“…Complex I biogenesis in eukaryotes is a complicated process dependent upon the coordinated expression of the nuclear and mitochondrial genomes (Guerrero‐Castillo et al, ). This process has attracted considerable attention as ~37% of OXPHOS disorders are characterized by isolated or combined complex I deficiency (Ghezzi & Zeviani, ; Rodenburg, ). Since the first report of human complex I deficiency by Morgan‐Hughes et al .…”

“…Complex I biogenesis in eukaryotes is a complicated process dependent upon the coordinated expression of the nuclear and mitochondrial genomes (Guerrero-Castillo et al, 2017). This process has attracted considerable attention as ~37% of OXPHOS disorders are characterized by isolated or combined complex I deficiency (Ghezzi & Zeviani, 2018;Rodenburg, 2016). Since the first report of human complex I deficiency by Morgan-Hughes et al in 1979, pathogenic mutations have been discovered in 20 (out of 37) nuclear-encoded subunits and all seven mitochondrially encoded subunits of complex I (Fiedorczuk & Sazanov, 2018;Friederich et al, 2017;Koopman et al, 2016;Rodenburg, 2016).…”