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Enhancing Mitochondrial Activity in Neurons Protects Against RESEARCH ARTICLE Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis Sina C Rosenkranz1, Artem A Shaposhnykov1, Simone Tra¨ ger1, Jan Broder Engler1, Maarten E Witte2,3, Vanessa Roth1, Vanessa Vieira1, Nanne Paauw3, Simone Bauer1, Celina Schwencke-Westphal1, Charlotte Schubert1, Lukas Can Bal1, Benjamin Schattling1, Ole Pless4, Jack van Horssen3, Marc Freichel5, Manuel A Friese1* 1Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; 3Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; 4Fraunhofer ITMP ScreeningPort, Hamburg, Germany; 5Institute of Pharmacology, Heidelberg University, Heidelberg, Germany Abstract While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1- *For correspondence: alpha (PGC-1a). In mice, neuronal overexpression of Ppargc1a, which encodes for PGC-1a, led to [email protected] increased numbers of mitochondria, complex IV activity, and maximum respiratory capacity. hamburg.de Moreover, Ppargc1a-overexpressing neurons showed a higher mitochondrial membrane potential Competing interests: The that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Ppargc1a authors declare that no aggravated neurodegeneration during experimental autoimmune encephalomyelitis, while neuronal competing interests exist. overexpression of Ppargc1a ameliorated it. Our study provides systemic insights into mitochondrial Funding: See page 21 dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy. Received: 05 August 2020 Accepted: 10 February 2021 Published: 10 February 2021 Reviewing editor: Brandon K Introduction Harvey, NIDA/NIH, United States Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) and the most frequent non-traumatic cause of neurological impairment during early adulthood. Neuronal Copyright Rosenkranz et al. loss occurs already from disease onset and correlates best with irreversible disability in MS patients This article is distributed under (Fisher et al., 2008; Fisniku et al., 2008; Tallantyre et al., 2010). While there has been substantial the terms of the Creative Commons Attribution License, progress in the understanding and treatment of the immune response, the pathogenesis of concur- which permits unrestricted use rent neuronal damage is incompletely understood. Recently, two drugs, ocrelizumab and siponimod, and redistribution provided that have been licensed for the treatment of progressive MS patients; however, their mode of action the original author and source are relies on immune regulation (Kappos et al., 2018; Montalban et al., 2017). Since there are currently credited. no therapies available to counteract the progression of neurodegeneration in MS patients Rosenkranz et al. eLife 2021;10:e61798. DOI: https://doi.org/10.7554/eLife.61798 1 of 26 Research article Immunology and Inflammation Neuroscience eLife digest Multiple sclerosis is a life-long neurological condition that typically begins when people are in their twenties or thirties. Symptoms vary between individuals, and within a single individual over time, but can include difficulties with vision, balance, movement and thinking. These occur because the immune system of people with multiple sclerosis attacks the brain and spinal cord. This immune assault damages neurons and can eventually cause them to die. But exactly how this happens is unclear, and there are no drugs available that can prevent it. One idea is that the immune attack in multiple sclerosis damages neurons by disrupting structures inside them called mitochondria. These cellular ‘organs’, or organelles, produce the energy that all cells need to function correctly. If the mitochondria fail to generate enough energy, the cells can die. And because neurons are very active cells with high energy demands, they are particularly vulnerable to the effects of mitochondrial damage. By studying a mouse version of multiple sclerosis, Rosenkranz et al. now show that mitochondria in the neurons of affected animals are less active than those of healthy control mice. This is because the genes inside mitochondria that enable the organelles to produce energy are less active in the multiple sclerosis mice. Most of these genes that determine mitochondrial activity and energy production are under the control of a single master gene called PGC-1alpha. Rosenkranz et al. showed that boosting the activity of this gene — by introducing extra copies of it into neurons — increases mitochondrial activity in mice. It also makes the animals more resistant to the effects of multiple sclerosis. Boosting the activity of mitochondria in neurons could thus be a worthwhile therapeutic strategy to investigate for multiple sclerosis. Future studies should examine whether drugs that activate PGC- 1alpha, for example, could help prevent neuronal death and the resulting symptoms of multiple sclerosis. (Dendrou et al., 2015; Feinstein et al., 2015) and repurposing of drugs to directly target neurode- generation in MS has been disappointing (Chataway et al., 2020), a better understanding of the molecular processes that determine neuronal cell loss in MS is urgently needed. Neuronal loss in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), has been associated with enhanced production of reactive oxygen and nitrogen species by immune cells and with increased iron accumulation in the gray matter (Stephenson et al., 2014). Both pro- cesses can lead to damage of neuronal mitochondria with subsequent metabolic failure (Campbell et al., 2011). Moreover, disruption of neuronal ion homeostasis (Craner et al., 2004; Friese et al., 2014) and aggregation of neuronal proteins (Schattling et al., 2019) consume high amounts of energy that might further drive neuroaxonal injury. Furthermore, excessive activation of calcium-dependent processes and neuronal calcium overload seems to be another important com- ponent of neuronal injury (Friese et al., 2007; Schattling et al., 2012; Witte et al., 2019). While identifying druggable targets that specifically induce neuronal resilience has been extremely difficult due to insufficient insights into key modulators, mitochondria could serve as an important hub as they are pivotal for both energy production and calcium homeostasis (Vafai and Mootha, 2012). Mitochondria usually have a high calcium buffering capacity, which is driven by their negative membrane potential that is generated by the activity of oxidative phosphorylation (Kann and Kova´cs, 2007; Zorova et al., 2018). However, overload of mitochondria with calcium as a conse- quence of CNS inflammation can result in inappropriate activation of the mitochondrial permeability transition pore (PTP) with subsequent mitochondrial swelling and cell death (Giorgi et al., 2018; Rizzuto et al., 2012), which is one of the neuropathological hallmarks in neurons during EAE (Nikic´ et al., 2011). Inhibiting the mitochondrial matrix protein cyclophilin D, a regulator of the PTP can partially counteract this dysregulation (Forte et al., 2007). Additionally, to counteract ion imbal- ance, a higher activity of ATP-dependent ion pumps would be required. However, postmortem stud- ies of MS patients’ CNS tissue revealed a compromised neuronal ATP production by oxidative phosphorylation as decreased mitochondria complex IV activity in demyelinated axons and neurons was detected (Campbell et al., 2011; Mahad et al., 2009). Similarly, mitochondrial gene expression Rosenkranz et al. eLife 2021;10:e61798. DOI: https://doi.org/10.7554/eLife.61798 2 of 26 Research article Immunology and Inflammation Neuroscience is suppressed in motor neurons of the spinal cord in EAE mice (Schattling et al., 2019), further sup- porting a comprised mitochondrial function during CNS inflammation. Thus, excess neuroaxonal calcium, together with mitochondrial dysfunction, has been postulated to trigger neuroaxonal injury observed in MS and EAE. This would be predicted to lead to elevated levels of calcium within neuronal and axonal mitochondria, further perpetuating mitochondrial dys- function and neuronal injury. However, it is currently unknown whether interventions that increase mitochondrial energy production in neurons can rescue neurodegeneration during CNS inflammation. Here, we discovered by an unsupervised survey of neuronal gene expression during CNS inflam- mation that genes involved in the electron transport chain (ETC), especially in complex I and IV, are repressed in motor neurons. While this is not accompanied by a decrease of mitochondrial numbers in motor neuronal somata, we detected a decrease in neuronal mitochondrial complex IV activity. This implies
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