Mitochondrial signaling in disease: from cancer to neurodegeneration

ATP, the major cellular energy currency, is primarily synthesized by mitochondria, through oxidative phosphorylation, and by the glycolytic pathway. Importantly, impairments in these fine-tuned metabolic processes are associated with multiple pathological conditions. In neurons, the rate of mitochondrial ATP synthesis is closely aligned with synaptic activity, highlighting the importance of mitochondria as the main powerhouse of excitable cells. In contrast, in several cancers, significant metabolic rewiring results in the boosting of glycolysis and the downregulation of mitochondrial respiration. In these cells, glycolysis and mitochondrial activity provide intermediate metabolites essential for cell proliferation and the epigenetic control of gene expression, as well as for post translational modifications. Remarkably, recent evidence demonstrates that mitochondria also represent key signaling hubs regulating multiple, often ATP-independent, cellular pathways, ranging from cell growth and differentiation to intercellular communication and cell death. Furthermore, mitochondria interact with different organelles and are both targets and shapers of key pathways such as ROS and calcium signaling, thus partaking in most of the physiological and pathological cell activities regulated by these signals.

Considering the crucial role of metabolism and mitochondrial physiology in the regulation of fundamental cell pathways, it is not surprising that their alterations have been associated with pathologies such as cancer and neurodegenerative disorders. However, in some cases, it is still unclear whether metabolic alterations underlie disease onset or are just epiphenomena following its progression. This is a challenging issue to address, especially because mitochondria: 1) are hubs where multiple signaling/metabolic pathways converge and interconnect; 2) engage highly dynamic physical and functional contacts with different intracellular organelles, exchanging metabolites and/or key information which control wide-ranging cell activities; 3) are regulated by and actively shape the homeostasis of pleiotropic intracellular second messengers such as Ca2+ and cyclic-AMP. Efforts to clarify these aspects are of utmost importance to further our knowledge of the molecular mechanisms underpinning disease onset and progression, and are fundamental for the design of specific and effective therapeutic strategies. Focusing on cancer and neurodegenerative disorders, the major goals of this special issue are: a) to provide new data or literature reviews linking alterations of metabolic and mitochondrial signaling with disease; b) to elucidate the contribution of altered interorganelle cross-talk to disease onset; c) to present approaches aimed at analysing/comparing pathological conditions, such as Alzheimer's and Parkinson's disease, characterized by partially similar mitochondrial alterations, but different phenotypes; d) to propose novel targets/treatments focused on mitochondria/metabolism.

We welcome contributions in the form of Research articles, reviews, mini-reviews or perspectives that cover, but are not limited to, the following topics in the context of cancer and/or neurodegenerative disorders: - Mechanisms and/or molecules underlying specific metabolic/mitochondrial alterations; - Alterations of the interplay between mitochondria and other organelles as key determinants of disease;
- Investigation of the role of mitochondrial metabolism in intercellular communication, particularly in the context of tumor microenvironment and neuroinflammation;
- Evaluation of the potential of metabolic alterations as biomarkers for early diagnosis;
- Signals leading to different diseases/phenotypes in the presence of common mitochondrial disturbances;
- Novel methods/tools/approaches for studying/predicting/rescuing/targeting mitochondrial functionality;
- Comparison of the disturbances in mitochondrial signaling and metabolism observed in different pathological conditions, highlighting novel disease-specific pathways;
- Consolidation of literature investigating specific aspects of metabolism/mitochondrial signaling in disease.


Conflict of interest declaration:
A patent application, including Francesco Ciscato as inventor, was licenced to the University of Padova for the use of Hexokinase 2-targeting peptides as an anti-neoplastic tool.