Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice

Abstract

Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed.

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…70,74 These data also support the notion that mitochondrial DNA genotype and nuclear-mitochondrial interactions are important determinants of higher cognitive tasks. 75 It is currently hard to quantify the relative contribution of excitatory and inhibitory neurons to energy utilization during gamma oscillations. Owing to the lack of cell-specific data and in the interest of simplicity, global energy budgets for gray matter have been based on glutamatergic neurons that provide 85% to 90% of the neuronal population in the cortical circuits.…”

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

“…The mitochondrial influences on complex diseases/traits are age-related, with increasing influence exerted in the elderly. 13 The mechanism underlying the association between UCP2 gene polymorphisms and chronic inflammatory diseases remain unknown. An important mediator in the pathway could be the mitochondria reactive oxygen species (ROS).…”

Visual perception and imagery: A new molecular hypothesis

“…Roubertoux et al provided direct evidence for the involvement of mtDNA in cognitive function (Roubertoux et al, 2003). Mitochondria have a central role in maintaining genomic stability and in controlling essential nuclear processes (Desler et al, 2007).…”

“…Mitochondria have a central role in maintaining genomic stability and in controlling essential nuclear processes (Desler et al, 2007). The function of mitochondria is controlled by interactions between nuclear and mitochondrial genes (Roubertoux et al, 2003;Chen and Stern, 2006). Oscillations of mitochondrial energy states occur as a consequence of the interplay between mitochondrial ROS production and ROS scavenging systems in cells (Cortassa et al, 2004).…”