Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases

Abstract

The total amount of cellular mitochondrial DNA (mtDNA) varies widely and seems to be related to the nature and metabolic state of tissues and cells in culture. It is not known, however, whether this variation has any significance in vivo, and to which extent it regulates energy production. To better understand the importance of the cellular mtDNA level, we studied the influence of a gradual reduction of mtDNA copy number on oxidative phosphorylation in two models: (a) a control human cell line treated with different concentrations of 2', 3'-dideoxycytidine, a nucleoside analogue that inhibits mtDNA replication by interfering with mitochondrial DNA polymerase gamma, and (b) a cell line derived from a patient presenting mtDNA depletion. The two models were used to construct biochemical and phenotypic threshold curves. Our results show that oxidative phosphorylation activities are under a tight control by the amount of mtDNA in the cell, and that the full complement of mtDNA molecules are necessary to maintain a normal energy production level.

Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers

“…Rocher et al . 60 indicated that the quantity of mtDNA in human cell lines is tightly correlated to CIV activity. Importantly, apparent excess of catalytic capacity does not signify that it is not functionally required, considering the importance for high affinity of mitochondria to oxygen 55, 61 and the role of CIV in the control of cytochrome reduction levels 62 .…”

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

“…These characteristics are compatible with the shift from hypoxia to anoxia, where mitochondria switch from producers to consumers of ATP without changing their mitochondrial mass 54 . Moreover, the mtDNA content and mtRNA levels decrease when mitochondria cease their energy production 55 . Taken together, these data indicate that day 4-anoxia-treated satellite cells display the hallmarks of anoxic mitochondria, and suggest that day 4 post mortem satellite cells might not be in an truly anoxic microenvironment.…”

Mitonuclear match: Optimizing fitness and fertility over generations drives ageing within generations

“…In essence, the reduction state of the inner membrane is the signal giver and output sensor for the reactive (as opposed to proactive) expression of mitochondrial genes. Certainly, translational regulation, protein stability, phosphorylation and supercomplex assembly all modulate respiratory rate; but these mechanisms ultimately revolve around transcriptional control, as demonstrated by the near-linear correlation between mtDNA copy number and respiratory rate [35]. This system enables respiratory stoichiometry to be calibrated locally to need, tailoring supply to demand.…”