Mitochondrial complex I activity is significantly decreased in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with mitochondrial DNA C3310T mutation: A cybrid study

Abstract 

Mitochondrial respiratory function in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with heteroplasmic mitochondrial DNA (mtDNA) C3310T mutation, which replaces the second amino acid of NADH dehydrogenase 1 (ND1) from a hydrophobic Proline to a hydrophilic Serine, was investigated. Mitochondrial respiratory function solely due to mtDNA C3310T mutation was investigated in cybrid system by the fusion of mtDNA-deleted (ρ⁰) HeLa cells and exogenous mtDNA either from the proband or from controls. Total oxygen consumption of the proband cybrid cells was significantly decreased compared with those of controls (2.468±0.475 versus 2.871±0.484μmol/h/10⁷ cells, p=0.0392). Mitochondrial respiratory chain complex I activity of the proband cybrid cells was also significantly decreased compared with those of controls (0.191±0.080 versus 0.288±0.113μmol/h/mg protein, p=0.0223). Furthermore, ATP content in the proband cybrid cells was also significantly decreased compared with those in controls (1.119±0.344 versus 1.419±0.378pmol/10⁵ cells, p=0.044). The present study indicates that mtDNA C3310T mutation may be a pathogenic mutation of maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy in the proband and the family.

Abbreviations: TTFA, thenoyltrifluoroacetone, G3P, glycerol-3-phosphate, TMPD, N,N,N′,N′-tetramethyl-p-phenylenediamine, I, complex I, II, complex II, III, compelx III, IV, complex IV

Keywords: MtDNA C3310T heteroplasmic mutation, Diabetes mellitus, Hypertrophic cardiomyopathy, Respiratory chain complex I, Cybrid cells