Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies

Abstract

Neurodegenerative diseases are a common late-life scourge for which disease-modifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed.

Figure 1

An integrated view of pathways involved in cell energy production.

Figure 2

In human neuroblastoma cells, glucose starvation increases mitochondrial respiration without inducing obvious mitochondrial biogenesis. The data in this figure were produced using an XF24 Flux Analzyer (Seahorse Biosciences). At the start of the experiment SH-SY5Y cells were maintained in either normal DMEM medium (control cells) or in DMEM containing no glucose (starved cells); at the time these measurements were taken the starved cell had been without glucose for 15 hours. Glucose starved cell metabolic physiology is indicated by orange lines, and control cell metabolic physiology is indicated by blue lines. Panel (A) shows the oxygen consumption rates (OCR) of cells maintained under the two conditions, and panel (B) shows the extracellular acidification rate (ECAR) that is mostly due to lactate excretion. After baseline OCR and ECAR values are established, glucose was injected in the mediums, and this had a profound effect on the starved but not the control cells. The glycolysis inhibitor 2-deoxyglucose was next injected, which rapidly increased the control cell OCR to the level it was in the 15 hour starved cells. This was followed by injection of the ATP synthase inhibitor oligomycin, which terminates coupled mitochondrial respiration. Lastly, the complex I and III inhibitors rotenone and myxothiazol were used to stop the residual uncoupled mitochondrial respiration, so only non-mitochondrial oxygen consumption remains. After oligomycin and again after rotenone and myxothiazol the OCR values for both the control and starved cells were similar, indicating in the experiment starved and control cell numbers were equivalent. Additional details pertaining to this experiment are provided in the text. 2 DG=2 deoxyglucose; oligo=oligomycin; rot=rotenone; myx=myxothiazol.