Abstract
A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP; Opa1+/−). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.
Highlights
Mitochondria play a critical role in cell death and survival (Fieni et al, 2012)
Mitochondrial morphology is controlled by mitochondrial fission and fusion, and in neurons this ensures the correct shape and distribution of mitochondria in relation to dendrite and synapse location
Many age-related neurodegenerative diseases are characterized by deficient mitochondrial renewal or dynamics as reviewed by Chan (2006)
Summary
Mitochondria play a critical role in cell death and survival (Fieni et al, 2012). Compromised mitochondrial function (Hedskog et al, 2013) is common in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease (Schon and Area-Gomez, 2013; Krols et al, 2016; Cai and Tammineni, 2017; Erpapazoglou et al, 2017). While neuronal metabolism accounts for $20% of the body’s total energy demand (Yu et al, 2018), mitochondrial respiration, which is least 15 times more efficient at ATP production than glycolysis (Rich, 2003), is largely responsible for meeting this demand. Neurons require large amounts of ATP to maintain ionic gradients across cell membranes and support synaptic transmission. Many age-related neurodegenerative diseases are characterized by deficient mitochondrial renewal or dynamics as reviewed by Chan (2006). Healthy ageing requires enough metabolic capacity to cope with stress and injury (Atamna et al, 2018). Reduction in flexibility of cellular transport or inability to meet peak-time metabolic demands results in cellular oxidative stress, senescence, cell type transformation, and, cell death (Chauhan et al, 2014; Rattan, 2015)
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