It is estimated that over 44 million people across the globe have dementia, and half of these cases are believed to be Alzheimer’s disease (AD). As the proportion of the global population which is over the age 60 increases so will the number of individuals living with AD. This will result in ever-increasing demands on healthcare systems and the economy. AD can be either sporadic or familial, but both present with similar pathobiology and symptoms. Three prominent theories about the cause of AD are the amyloid, tau and mitochondrial hypotheses. The mitochondrial hypothesis focuses on mitochondrial dysfunction in AD, however little attention has been given to the potential dysfunction of the mitochondrial ATP synthase in AD. ATP synthase is a proton pump which harnesses the chemical potential energy of the proton gradient across the inner mitochondrial membrane (IMM), generated by the electron transport chain (ETC), in order to produce the cellular energy currency ATP. This review presents the evidence accumulated so far that demonstrates dysfunction of ATP synthase in AD, before highlighting two potential pharmacological interventions which may modulate ATP synthase.

Mitochondrial dysfunction is evident in numerous neurodegenerative and age-related disorders. It has also been linked to cellular ageing, however our current understanding of the mitochondrial changes that occur are unclear. Functional studies have made some progress reporting reduced respiration, dynamic structural modifications and loss of membrane potential, though there are conflicts within these findings. Proteomic analyses, together with functional studies, are required in order to profile the mitochondrial changes that occur with age and can contribute to unravelling the complexity of the ageing phenotype. The emergence of improved protein separation techniques, combined with mass spectrometry analyses has allowed the identification of age and cell-type specific mitochondrial changes in energy metabolism, antioxidants, fusion and fission machinery, chaperones, membrane proteins and biosynthesis pathways. Here, we identify and review recent data from the analyses of mitochondria from rodent brains. It is expected that knowledge gained from understanding age-related mitochondrial changes of the brain should lead to improved biomarkers of normal ageing and also age-related disease progression.

It is accepted that smaller mammals with higher metabolic rates have shorter lifespans. The very few species that do not follow these rules can give insights into interesting differences. The recorded maximum lifespans of bats are exceptional - over 40 years, compared with the laboratory mouse of 4 years. We investigated the differences in the biochemical composition of mitochondria between bat and mouse species. We used proteomics and ultra-high-performance liquid chromatography coupled with high resolution mass spectrometry lipidomics, to interrogate mitochondrial fractions prepared from Mus musculus and Pipistrellus pipistrellus brain and skeletal muscle. Fatty acid binding protein 3 was found at different levels in mouse and bat muscle mitochondria and its orthologues were investigated in Caenorhabditis elegans knock-downs for LBP 4, 5 and 6. In the bat, high levels of free fatty acids and N-acylethanolamine lipid species together with a significantly greater abundance of fatty acid binding protein 3 in muscle (1.8-fold, p =0.037) were found. Manipulation of fatty acid binding protein orthologues in C. elegans suggest these proteins and their role in lipid regulation are important for mitochondrial function.

Response to inflammation is a key determinant in many diseases and their outcomes. Diseases that commonly affect older people are frequently associated with altered inflammatory processes. Neuroinflammation has been described in Parkinson's disease (PD) brain. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and at the sub-cellular level, mitochondrial dysfunction is a key feature. However, there is evidence that a different region of the brain, the cerebellum, is involved in the pathophysiology of PD. We report relative levels of 40 pro-and anti-inflammatory cytokines measured in PD and control cerebellar mitochondria. These data were obtained by screening cytokine antibody arrays. In parallel, we present concentrations of 29 oxylipins and 4 endocannabinoids measured in mitochondrial fractions isolated from post-mortem PD cerebellum with age and sex matched controls. Our oxylipin and endocannabinoid data were acquired via quantitation by LC-ESI-MS/MS. The separate sample sets both show there are clearly different inflammatory profiles between the sexes in control samples. Sex specific profiles were not maintained in cerebellar mitochondria isolated from PD brains.

One of the genes which has been linked to the onset of juvenile/early onset Parkinson's disease (PD) is PINK1. There is evidence that supports the therapeutic potential of exercise in the alleviation of PD symptoms. It is possible that exercise may enhance synaptic plasticity, protect against neuro-inflammation and modulate L-Dopa regulated signalling pathways. We explored the effects of exercise on Pink1 deficient Drosophila melanogaster which undergo neurodegeneration and muscle degeneration. We used a 'power-tower' type exercise platform to deliver exercise activity to Pink1and age matched wild-type Drosophila. Mitochondrial proteomic profiles responding to exercise were obtained. Of the 516 proteins identified, 105 proteins had different levels between Pink1and wild-type non-exercised Drosophila. Gene ontology enrichment analysis and STRING network analysis highlighted proteins and pathways with altered expression within the mitochondrial proteome. Comparison of the Pink1exercised proteome to wild-type proteomes showed that exercising the Pink1 -Drosophila caused their proteomic profile to return towards wild-type levels.