Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders

Abstract

Altered mitochondrial energy metabolism contributes to the pathophysiology of acute brain injury caused by ischemia, trauma, and neurotoxins and by chronic neurodegenerative disorders such as Parkinson's and Huntington's diseases. Although much evidence supports that the electron transport chain dysfunction in these metabolic abnormalities has both genetic and intracellular environmental causes, alternative mechanisms are being explored. These include direct, reversible inhibition of cytochrome oxidase by nitric oxide, release of mitochondrial cytochrome c, oxidative inhibition of mitochondrial matrix dehydrogenases and adenine nucleotide transport, the availability of NAD for dehydrogenase reactions, respiratory uncoupling by activities such as that of the permeability transition pore, and altered mitochondrial structure and intracellular trafficking. This review focuses on the catabolism of neuronal NAD and the release of neuronal mitochondrial NAD as important contributors to metabolic dysfunction. In addition, the relationship between apoptotic signaling cascades and disruption of mitochondrial energy metabolism is considered in light of the fine balance between apoptotic and necrotic neural cell death.

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

“…Deficient mitochondrial activities are indicated in chronic human neuropathologies such as aging and age-related neurodegenerative diseases whereas hyperactive mitochondrial activity and ionic stress are implicated in acute conditions after traumatic brain injury. 10 Hence, mitochondria in vivo can be viable drug targets to favorably modulate (increase or decrease) neuronal and hemodynamic activities in human neuropathology.…”

“…[4][5][6][7][8] Characterized mostly in vitro, the impact of mitochondrial Ca 2 þ cycling activity on brain function in vivo is still largely unexplored. As both deficient 9,10 and hyperactive mitochondrial metabolism 11,12 are implicated in neuropathology, a systems-level assessment of mitochondrial functional impact on central nervous system responses, possibly through translatable measures, is important.…”

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

“…In particular, positron emission tomography imaging studies have shown that glucose utilization is dramatically lower in AD, compared to aged‐matched, nondemented brain (Mosconi et al ., 2009; Landau et al ., 2012). Moreover, postmortem analysis of AD brain shows down‐regulated expression of mitochondrial enzymes indicating a deficiency in energy metabolism (Soane et al ., 2007). …”

Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction

“…Thus, alterations in cardiolipin (CL) content and molecular species composition regulate electron transport chain efficiency, apoptosis, and mitochondrial signaling (reviewed in Refs. 27,28).…”