Calcium-mediated mitochondrial energy deficiency in Parkinson's and Alzheimer's diseases: Insights from computational modelling

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative disorders worldwide and are characterised by progressive cognitive and functional impairments caused by neuronal loss. Energy deficiency is a predominant hallmark of their pathophysiology and plays a central role in the development of the disease, notably by mitochondrial dysfunction enhancing protein aggregation and oxidative stress which trigger subsequently immune responses and neuronal loss. Quantifying this energetic deficiency and identifying specific causative mechanisms from the complex network of interacting metabolic and regulatory pathways at play is rather challenging, where integrative mathematical modelling represents a powerful tool to support these investigations. Here, we review the latest developments in integrative modelling in brain bioenergetics in relation to Alzheimer's and Parkinson's diseases where we focus on the regulatory role of Ca 2+ signalling. Finally, we discuss recent challenges and future directions to improve the current understanding of the energy-deficiency theory of neurodegeneration. • Mechanistic models help to dissect causal relationships in neurodegen-eration. • Energy deficiency and Ca 2+ alterations emerge as pillars in neurode-generation. • Next-generation models consider immunometabolic and systems-level aspects. • Multiscale models offer a great potential for translational applications.