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Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, however, remain poorly elucidated. With the perspective to grasp the molecular pathways of neurodegeneration occurring in prion diseases, and to identify therapeutic targets, achieving a better understanding of PrPC roles is a priority. Based on global approaches that compare the proteome and metabolome of the PrPC expressing 1C11 neuronal stem cell line to those of PrPnull-1C11 cells stably repressed for PrPC expression, we here unravel that PrPC contributes to the regulation of the energetic metabolism by orienting cells towards mitochondrial oxidative degradation of glucose. Through its coupling to cAMP/protein kinase A signaling, PrPC tones down the expression of the pyruvate dehydrogenase kinase 4 (PDK4). Such an event favors the transfer of pyruvate into mitochondria and its conversion into acetyl-CoA by the pyruvate dehydrogenase complex and, thereby, limits fatty acids β-oxidation and subsequent onset of oxidative stress conditions. The corruption of PrPC metabolic role by pathogenic prions PrPSc causes in the mouse hippocampus an imbalance between glucose oxidative degradation and fatty acids β-oxidation in a PDK4-dependent manner. The inhibition of PDK4 extends the survival of prion-infected mice, supporting that PrPSc-induced deregulation of PDK4 activity and subsequent metabolic derangements contribute to prion diseases. Our study posits PDK4 as a potential therapeutic target to fight against prion diseases., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.M.L has non-financial competing interests with Hoffmann La Roche Ltd laboratories. He acts as an expert witness for Hoffmann La Roche Ltd laboratories.

Microbes have developed a series of strategies to overcome the defense mechanisms of the infected host. During pathogen-host coevolution, they develop strategy to manipulate cellular machinery particularly in subverting mitochondrion function. Mitochondria are highly dynamic organelles that constantly remodel their structure. In particular, shaping and cellular distribution of the mitochondrial network is maintained in large part by the conserved activities of mitochondrial division, fusion, motility, and tethering. Mitochondria have been long recognized for their role in providing energy production, calcium metabolism, and apoptosis. More recently, mitochondria have been also shown to serve as a platform for innate immune response. In this context, mitochondrial dynamics and shaping is not only essential to maintain cristae structure and bioenergetic to fuel cellular demands but contribute to regulate cellular function such as innate immune response and mitochondrial permeabilization. Due to their key role in cell survival, mitochondria represent attractive targets for pathogens. Therefore, microbes by manipulating mitochondrial dynamics may escape to host cellular control. Herein, we describe how mitochondrial bioenergetics, dynamics, and shaping are impacted during microbe infections and how this interplay benefits to pathogens contributing to the diseases.