NDUFAF3 variants that disrupt mitochondrial complex I assembly may associate with cavitating leukoencephalopathy

Abstract

Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a 1-year-old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17% to 21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C > A:p.Pro169Thr). Two-dimensional, blue-native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate-PAGE revealed reductions in Q-module (NDUFS2, NDUFS3, and NDUFA9) and P-module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3.

Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain

“…Pathological variants causing CI deficiency have been described in NDUFAF1 [CIA30], ACAD9, and TMEM126B that together with ECSIT, COA1 and TMEM186, form the Mitochondrial Complex I Intermediate Assembly (MCIA) [ 172 ] important for the biogenesis of the ND2-module. NDUFAF3 (C3ORF60) and NDUFAF4 (C6ORF66) working together in the assembly of the Q-module, have been found mutated in different cases of infantile mitochondrial disease [ 150 , 151 , 228 , 229 , 230 , 231 ].…”

Homeostatic control of nuclear-encoded mitochondrial gene expression by the histone variant H2A.Z is essential for neuronal survival

“…Among the DEGs with known functions in the organelle are those that encode for complex I subunits (Ndufb7, Ndufb8, Ndufs8), complex I assembly factors (Ndufaf1, Ndufaf3, Nudufaf5), small (Mrps11, Mrps22, Mrps23) and large mitoribosome subunits (Mrpl3, Mrpl15, Mrpl28), and mitoribosome assembly factors (Fastkd2, Malsu1, Ddx28) (Figures 3D-3H). Interestingly, mutations in many of these genes, including Mrps22, Fastkd2, Ndufs8, Ndufb8, Ndufaf3, and Ndufaf5, have previously been implicated in neurological disorders (Loeffen et al, 1998;Kılıç et al, 2017;Yoo et al, 2017;Ishiyama et al, 2018;Piekutowska-Abramczuk et al, 2018;Bi et al, 2021).…”