Mild mitochondrial metabolic deficits by α-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease.

Brain activities of the mitochondrial enzyme α-ketoglutarate dehydrogenase complex (KGDHC) are reduced in Alzheimer's disease and other age-related neurodegenerative disorders. The goal of the present study was to test the consequences of mild impairment of KGDHC on the structure, protein signaling and dynamics (mitophagy, fusion, fission, biogenesis) of the mitochondria. Inhibition of KGDHC reduced its in situ activity by 23-53% in human neuroblastoma SH-SY5Y cells, but neither altered the mitochondrial membrane potential nor the ATP levels at any tested time-points. The attenuated KGDHC activity increased translocation of dynamin-related protein-1 (Drp1) and microtubule-associated protein 1A/1B-light chain 3 (LC3) from the cytosol to the mitochondria, and promoted mitochondrial cytochrome c release. Inhibition of KGDHC also increased the negative surface charges (anionic phospholipids as assessed by Annexin V binding) on the mitochondria. Morphological assessments of the mitochondria revealed increased fission and mitophagy. Taken together, our results suggest the existence of the regulation of the mitochondrial dynamism including fission and fusion by the mitochondrial KGDHC activity via the involvement of the cytosolic and mitochondrial protein signaling molecules. A better understanding of the link among mild impairment of metabolism, induction of mitophagy/autophagy and altered protein signaling will help to identify new mechanisms of neurodegeneration and reveal potential new therapeutic approaches.

Abnormal Glucose Metabolism in Alzheimer's Disease: Relation to Autophagy/Mitophagy and Therapeutic Approaches.

Diminished glucose metabolism accompanies many neurodegenerative diseases including Alzheimer's disease. An understanding of the relation of these metabolic changes to the disease will enable development of novel therapeutic strategies. Following a metabolic challenge, cells generally conserve energy to preserve viability. This requires activation of many cellular repair/regenerative processes such as mitophagy/autophagy and fusion/fission. These responses may diminish cell function in the long term. Prolonged fission induces mitophagy/autophagy which promotes repair but if prolonged progresses to mitochondrial degradation. Abnormal glucose metabolism alters protein signaling including the release of proteins from the mitochondria or migration of proteins from the cytosol to the mitochondria or nucleus. This overview provides an insight into the different mechanisms of autophagy/mitophagy and mitochondrial dynamics in response to the diminished metabolism that occurs with diseases, especially neurodegenerative diseases such as Alzheimer's disease. The review discusses multiple aspects of mitochondrial responses including different signaling proteins and pathways of mitophagy and mitochondrial biogenesis. Improving cellular bioenergetics and mitochondrial dynamics will alter protein signaling and improve cellular/mitochondrial repair and regeneration. An understanding of these changes will suggest new therapeutic strategies.