Mitochondrial respiratory chain protein co-regulation in the human brain
Caroline Trumpff,
Edward Owusu-Ansah,
Hans-Ulrich Klein,
Annie J. Lee,
Vladislav Petyuk,
Thomas S. Wingo,
Aliza P. Wingo,
Madhav Thambisetty,
Luigi Ferrucci,
Nicholas T. Seyfried,
David A. Bennett,
Philip L. De Jager,
Martin Picard
Affiliations
Caroline Trumpff
Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, USA
Edward Owusu-Ansah
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, USA
Hans-Ulrich Klein
Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, USA
Annie J. Lee
Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, USA
Vladislav Petyuk
Pacific Northwest National Laboratory, Richland, Washington State, USA
Thomas S. Wingo
Departments of Neurology and Human Genetics, Emory University, Atlanta, GA, USA
Aliza P. Wingo
Atlanta VA Medical Center, Decatur, GA, USA; Department of Psychiatry, Emory University, Atlanta, GA, USA
Madhav Thambisetty
Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging Intramural Research Program, Baltimore, USA
Luigi Ferrucci
Longitudinal Study Section, National Institute on Aging, Baltimore, USA
Nicholas T. Seyfried
Department of Biochemistry, Emory University, Atlanta, USA
David A. Bennett
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Philip L. De Jager
Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, USA
Martin Picard
Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, USA; Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, USA; New York State Psychiatric Institute, New York, USA; Corresponding author.
Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer's disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2–4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.
