Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.

Observations of nerve axons in vivo reveal that electrical activity increases the number and speed of transported mitochondria, showing how sudden increases in energy demand may be satisfied.

Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-cells depends on Ca influx through high voltage-gated Ca channels (HVCCs). Ca influx also regulates insulin synthesis and insulin granule priming and contributes to β-cell electrical activity. The HVCCs are multisubunit protein complexes composed of a pore-forming α and auxiliary β and αδ subunits. αδ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of αδ-1, the dominant αδ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the αδ-1 subunit reduces the Ca currents through all HVCC isoforms expressed in β-cells equally in male and female mice. The reduced Ca influx alters the kinetics and amplitude of the global Ca response to glucose in pancreatic islets and significantly reduces insulin release in both sexes. The progression of diabetes in males is aggravated by a selective loss of β-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most αδ-1 female mice. Together, these findings demonstrate that the loss of the Ca channel αδ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.