Region-Specific Expression of Mitochondrial Complex I Genes during Murine Brain Development

Abstract

Mutations in the nuclear encoded subunits of mitochondrial complex I (NADH:ubiquinone oxidoreductase) may cause circumscribed cerebral lesions ranging from degeneration of the striatal and brainstem gray matter (Leigh syndrome) to leukodystrophy. We hypothesized that such pattern of regional pathology might be due to local differences in the dependence on complex I function. Using in situ hybridization we investigated the relative expression of 33 nuclear encoded complex I subunits in different brain regions of the mouse at E11.5, E17.5, P1, P11, P28 and adult (12 weeks). With respect to timing and relative intensity of complex I gene expression we found a highly variant pattern in different regions during development. High average expression levels were detected in periods of intense neurogenesis. In cerebellar Purkinje and in hippocampal CA1/CA3 pyramidal neurons we found a second even higher peak during the period of synaptogenesis and maturation. The extraordinary dependence of these structures on complex I gene expression during synaptogenesis is in accord with our recent findings that gamma oscillations – known to be associated with higher cognitive functions of the mammalian brain – strongly depend on the complex I activity. However, with the exception of the mesencephalon, we detected only average complex I expression levels in the striatum and basal ganglia, which does not explain the exquisite vulnerability of these structures in mitochondrial disorders.

Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients

“…Increased complex I gene expression in the cortex has been seen during cerebral development. This is related to intense neurogenesis, neuronal differentiation and migration 32. Our findings could thus support the hypothesis that proposes an important role for complex I activity in the neurogenesis and neuroplasticity of specific areas in the human brain; compromised complex I gene expression may therefore lead to primary cortical degeneration 33…”

Differential Alterations of the Mitochondrial Morphology and Respiratory Chain Complexes during Postnatal Development of the Mouse Lung

“…Comparable to our results, Bates and colleagues [ 51 ] detected a significant increase in the activity of complex I in the rat brain from postnatal day 1 to day 21, suggesting that the increase is due to the high demand for mitochondrial ATP during the brain development. Interestingly, not only mitochondrially encoded complex I subunits increased in the expression during the postnatal development as was shown by our study but also the nuclear-encoded mitochondrial subunits as was revealed by Wirtz and Schuelke [ 53 ]. In their study on the expression of the 33 nuclear-encoded complex I genes during postnatal development of the C57BL/6J mouse brain, they found the rise of expression intensity of the complex I around P11 in comparison to earlier stages and this coincided with the synaptogenesis [ 53 , 83 – 85 ].…”

“…However, to date, no detailed combined molecular and morphological analysis has been performed on the mitochondrial compartment during postnatal development of the mouse lung. Postnatal alterations of the mitochondrial compartment and its respiratory function have been mainly described in rat liver and muscle [ 28 , 39 – 44 ], pig skeletal muscle [ 45 ], rat, rabbit, and bovine hearts [ 43 , 46 – 49 ], mouse blood lymphocytes [ 50 ], and rat and mouse brain [ 51 – 53 ]. Therefore, here, we analyzed mitochondrial alterations during postnatal development (newborn, P15, and adult) of the mouse lung.…”

Energy and Potassium Ion Homeostasis during Gamma Oscillations

“…Intriguingly, the electrophysiological and bioenergetic features of the hippocampal CA3 network, i.e., highest levels in gamma oscillation power, oxygen consumption, and mitochondrial performance, also correlated with the highest expression of complex I subunits (Kann et al, 2011 ; Wirtz and Schuelke, 2011 ). Complex I (NADH:ubiquinone oxidoreductase) is a member of the respiratory chain in mitochondria.…”