Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.

Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased α-ketoglutarate (αKG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation

Neuronal loss of NCLX-dependent mitochondrial calcium efflux mediates age-associated cognitive decline

Summary: Mitochondrial calcium overload contributes to neurodegenerative disease development and progression. We recently reported that loss of the mitochondrial sodium/calcium exchanger (NCLX), the primary mechanism of mCa2+ efflux, promotes mCa2+ overload, metabolic derangement, redox stress, and cognitive decline in models of Alzheimer’s disease (AD). However, whether disrupted mCa2+ signaling contributes to neuronal pathology and cognitive decline independent of pre-existing amyloid or tau pathology remains unknown. Here, we generated mice with neuronal deletion of the mitochondrial sodium/calcium exchanger (NCLX, Slc8b1 gene), and evaluated age-associated changes in cognitive function and neuropathology. Neuronal loss of NCLX resulted in an age-dependent decline in spatial and cued recall memory, moderate amyloid deposition, mild tau pathology, synaptic remodeling, and indications of cell death. These results demonstrate that loss of NCLX-dependent mCa2+ efflux alone is sufficient to induce an Alzheimer’s disease-like pathology and highlights the promise of therapies targeting mCa2+ exchange

Cadaveric dissection and prosection of the nervous system

Introduction: Physical involvement in cadaveric dissections has been correlated with higher written and practical test scores and improvements in visual-spatial aptitude in medical students. In addition to technical dissections skills, cadaveric dissection also promotes habits of inquiry and improvement, and further formation of personal and professional identities. In 2014, a survey of medical school anatomy course directors revealed that 100% utilize cadavers in their anatomy curriculum, with nearly 85% following regionally organized approaches, rather than systems-based approaches. Regional-based approaches focus on teaching the anatomy and function of a specific region of the body in isolation from other regions, whereas system-based approaches focus on interrelationships of a system’s different parts throughout the body. While both learning approaches have their advantages and disadvantages, it is inherently more difficult to appreciate entire organ systems when dissecting in a region-by-region pattern. These authors sought to develop a dissection protocol for the human nervous system to expand upon our education in neuroanatomy. Methods: This study was conducted at Philadelphia College of Osteopathic Medicine in Philadelphia, Pennsylvania, according to the guidelines of the State Anatomical Board of Pennsylvania (SAP). Tools used for this dissection include those standard to most anatomy labs (scalpels, scissors, forceps, etc) as well as Virchow skull crushers, Kerrison and Leur rongeurs, bone chisels, rubber mallets, and a Dremel 3000. Ten medical students were divided into one of three dissection teams: the ‘Brain Team’ was responsible for structures above the vertebral level of C7, the ‘Spine Team’ were responsible for structures between the vertebral level of T1 and the lumbosacral plexus, and the ‘Peripheral Nerve Team’ were responsible for the brachial plexus, lumbosacral plexus, and their distal nerves. The dissection of all structures took about 18 working days. Each student volunteered about 20 hours per week. Results: The entirety of the CNS was preserved, including the cranial nerves, the eyes and their attachment to the brain, and the dural covering of the brain and spinal cord. The circle of Willis and its major branches were preserved under the dura. All spinal nerves from C1 to the coccygeal nerve were preserved bilaterally. Cutting the dura overlying the spinal cord and nerve roots revealed well-preserved dorsal and ventral rootlets, as well as cauda equina and filum terminale. The brachial and sacral plexuses were dissected from their origin at the spinal cord, down their major nerve branches to the hands and feet. The sympathetic chain was preserved from T1-T12, maintaining its connection with dorsal root ganglia, grey and white rami communicans, and the sympathetic trunk. Discussion: This protocol details an efficient method in dissection and generation of a single prosection of the major components of the human nervous system. Applications for this protocol are broad, ranging from long-term preservation of the prosection for use as a teaching aid to creation of an advanced anatomy elective including similar systems-based dissections. It is these authors’ hopes that this protocol may inform curriculum development and ultimately improve medical education of the nervous system