Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies

Abstract

Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency. Here, we report a second patient with UQCC2 deficiency. This girl was born prematurely; pregnancy was complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, and died at day 33. She had profound lactic acidosis and elevated urinary pyruvate. Exome sequencing revealed two homozygous missense variants in UQCC2, leading to a severe reduction of UQCC2 protein. Deficiency of complexes I and III was found enzymatically and on the protein level. A review of the literature on genetically distinct complex III defects revealed that, except TTC19 deficiency, the biochemical pattern was very often a combined respiratory chain deficiency. Besides complex III, typically, complex I was decreased, in some cases complex IV. In accordance with previous observations, the presence of assembled complex III is required for the stability or assembly of complexes I and IV, which might be related to respirasome/supercomplex formation.

Respiratory supercomplexes act as a platform for complex III ‐mediated maturation of human mitochondrial complexes I and IV

“…This confirmed the well-established connection between severe cIII 2 deficiency and cI impairment. Interestingly, the activity of cIV was also significantly reduced in our system, as previously reported in a subset of patients with severe cIII deficiency (Carossa et al, 2014;Feichtinger et al, 2017). Accordingly, the absence of fully assembled cIII 2 led to the complete loss of SCs containing cIII 2 and cI, and to the accumulation of an inactive pre-cI lacking the catalytic N-module; fully assembled cIV levels were also decreased and, to a lesser extent, those of cII as well.…”

“…Structurally, cIII 2 is part of all known respiratory supercomplexes (SCs), where it physically interacts with both cI and cIV in the SCs cI+cIII 2 +cIV n (Schagger & Pfeiffer, 2000), structures known as "respirasomes" because they are in principle able to transfer electrons from NADH to O 2 (Acin-Perez et al, 2008;Gu et al, 2016;Letts et al, 2016;Wu et al, 2016;Guo et al, 2017). It is well known that severe cIII 2 deficiency in patients carrying null mutations in genes encoding some cIII 2 structural components and assembly factors are associated with a concomitant decrease in cI activity (Lamantea et al, 2002;Bruno et al, 2003;Acin-Perez et al, 2004;Barel et al, 2008;Tucker et al, 2013;Carossa et al, 2014;Feichtinger et al, 2017) and, in some cases, in cIV activity as well (Carossa et al, 2014). These pleiotropic effects have been traditionally interpreted as a loss of cI and cIV stability in the absence of their SC partner (Acin-Perez et al, 2004), which is based on the premise that the biogenesis of MRC SCs proceeds by the incorporation of pre-made fully assembled individual complexes (Acin-Perez et al, 2008).…”

Human diseases associated with defects in assembly of OXPHOS complexes

“…Recently, a second case was published: a girl with respiratory distress and severe epileptic seizures, born after a pregnancy complicated by intrauterine growth retardation and oligohydramnios, who died at 1 month of age. Two homozygous missense variants in UQCC2 were identified, and a severe reduction in UQCC2 protein was demonstrated [ 85 ].…”

“…Indeed, multiple OXPHOS deficiency or impairment of supercomplexes have been already reported in some cases harboring mutations in genes encoding known assembly factors for ‘single’ complexes: e.g. NDUFAF2 [ 19 ], NDUFAF5 [ 28 ], UQCC2 [ 85 ], UQCC3 [ 87 ], COA7 [ 99 ].…”

Reduced Levels of ATP Synthase Subunit ATP5F1A Correlate with Earlier‐Onset Prostate Cancer

“…Combined OXPHOS deficiencies can arise from mitochondrial tRNA mutations, mtDNA deletions, and mtDNA depletion [ 19 ]. Since respiratory chain complexes are further organized into super/megacomplexes, mutations in complex III subunits typically also lead to secondary loss of complex I [ 20 ]. Furthermore, mutations in a number of genes involved in mitochondrial biogenesis, architecture, or protein transport can cause combined defects [ 19 ].…”