Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in <i>FUS</i> ALS Motoneurons
Vitaly L. Zimyanin,
Anna-Maria Pielka,
Hannes Glaß,
Julia Japtok,
Dajana Großmann,
Melanie Martin,
Andreas Deussen,
Barbara Szewczyk,
Chris Deppmann,
Eli Zunder,
Peter M. Andersen,
Tobias M. Boeckers,
Jared Sterneckert,
Stefanie Redemann,
Alexander Storch,
Andreas Hermann
Affiliations
Vitaly L. Zimyanin
Department of Molecular Physiology and Biological Physics, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
Anna-Maria Pielka
Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
Hannes Glaß
Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
Julia Japtok
Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
Dajana Großmann
Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
Melanie Martin
Institute of Physiology, Technische Universität Dresden, 01307 Dresden, Germany
Andreas Deussen
Institute of Physiology, Technische Universität Dresden, 01307 Dresden, Germany
Barbara Szewczyk
Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
Chris Deppmann
Department of Biology, Graduate School of Arts and Sciences, University of Virginia, Charlottesville, VA 22902, USA
Eli Zunder
Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, VA 22902, USA
Peter M. Andersen
Department of Clinical Sciences, Neurosciences, Umeå University, SE-901 85 Umeå, Sweden
Tobias M. Boeckers
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm Site, 89081 Ulm, Germany
Jared Sterneckert
Centre for Regenerative Therapie, Technische Universität Dresden, 01307 Dresden, Germany
Stefanie Redemann
Department of Molecular Physiology and Biological Physics, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
Alexander Storch
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, 18147 Rostock, Germany
Andreas Hermann
Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS models and can critically affect survival and the proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression is not fully understood yet. Here, we utilize hiPCS-derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in fused in sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons are accompanied by an overall upregulation of mitochondrial components and a significant increase in metabolic rates that correspond to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of diseased motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mitochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments, with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts the metabolic states of motoneurons and makes them more susceptible to further neurodegenerative mechanisms.
