A unique combination of rare mitochondrial ribosomal RNA variants affects the kinetics of complex I assembly.
Mitochondrial DNA (mtDNA) mutations in respiratory complexes subunits contribute to a large spectrum of human diseases. Nonetheless, ribosomal RNA variants remain largely under-investigated from a functional point of view. We here report a unique combination of two rare mitochondrial rRNA variants detected by serendipity in a subject with chronic granulomatous disease and never reported to co-occur within the same mitochondrial haplotype. In silico prediction of the mitochondrial ribosomal structure showed a dramatic rearrangement of the rRNA secondary structure. Functional investigation of cybrids carrying this unique haplotype demonstrated that the co-occurrence of the two rRNA variants determines a slow-down of the mitochondrial protein synthesis, especially in cells with an elevated metabolic rate, which impairs the assembly kinetics of Complex I, induces a bioenergetic defect and stimulates reactive oxygen species production. In conclusion, our results point to a sub-pathogenic role for these two rare mitochondrial rRNA variants, when found in the unique combination here reported in a single individual.
Dip. Farmacia e Biotecnologie (FABIT), Università di Bologna, via Irnerio 42, 40126 Bologna, Italy; Centro Interdipartimentale di Ricerca Industriale Scienze della Vita e Tecnologie per la Salute, Università di Bologna, 40100 Bologna, Italy.
Anna Maria
AM
Porcelli
Dip. Farmacia e Biotecnologie (FABIT), Università di Bologna, via Irnerio 42, 40126 Bologna, Italy.
Maria Antonietta
MA
Calvaruso
Dip. Farmacia e Biotecnologie (FABIT), Università di Bologna, via Irnerio 42, 40126 Bologna, Italy.
Luisa
L
Iommarini
Dip. Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy.
Ivana
I
Kurelac
Dip. Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy.
Roberta
R
Zuntini
Dip. Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy.
Simona
S
Ferrari
Dip. Scienze Mediche e Chirurgiche (DIMEC), U.O. Genetica Medica, Pol. Universitario S. Orsola-Malpighi, Università di Bologna, via Massarenti 9, 40138 Bologna, Italy. Electronic address: giuseppe.gasparre@gmail.com.
Giuseppe
G
Gasparre
D001483:Base Sequence; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000378:metabolism*; D006105:Granulomatous Disease, Chronic / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D012335:RNA, Ribosomal / Q000235:genetics*
D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; D042967:Electron Transport Complex I
Bioenergetics; Mitochondrial protein synthesis; Mitochondrial rRNA mutations; Ribosomal structure