Assembly of mitochondrial supercomplexes in the brain of a rat model of Alzheimer

NOVACK, GISELA V.; GALEANO P; CASTAÑO E.M; CUELLO, A CLAUDIO; MORELLI LAURA

ROANOKE

Congreso; Bi Annual Congress ASN 2022; 2022

The electron transport chain is made up of three main protein complexes (complexes I, III, IV) and several "auxiliary" complexes, plus a variety of electron donors and acceptors. Three models of organization of the main Complexes were postulated: FLUID, SOLID AND PLASTIC. In cognitive areas of the brain affected by abnormal Aβ deposition, mitochondria disrupt SCx assembly, promoting mitochondrial dysfunction. The animal model used is McGill-Thy1-APP rats in early stages of the pathology, the assembly of SCxs and the enzymatic activity of IC isolated and associated as SCxs were studied. For this, 1) DISSECTION of the cortex and hippocampus of 12-month-old WT and Tg rats; 2) ISOLATION of mitochondria by DIFFERENTIAL CENTRIFUGATION; 3) SOLUBILIZATION of mitochondria with digitonin to disaggregate SCX; 4) BN-PAGE to separate the SCX maintaining its organization, without altering its structure; 5) IC gel activity (isolated or assembled on SCxs). Substrate: NADH, pH 7.4. chromophore: NBT; 6) DENSITOMETRIC ANALYSIS: GELPRO; 7) STATISTICS: GraphPad Prims (T test). Results obtained so far using BN-PAGE, the abundance of SCxs was analyzed and it was observed that both genotypes: 1) assemble SC1; SC4 (respirosome) and SC5; 2) show the same amount of IC and SC1 and a significant decrease in the abundance of SC4 and SC5 in the cortex compared to the hippocampus. When the enzymatic activity was analyzed, it was observed that both genotypes present the same activity of SC4 (respirosome) and SC5. Tg rats show compared to WT: 1) a significant decrease in SC1 activity in the cortex and hippocampus. That is why we conclude that our results support the plastic model of Mitochondrial Complex Organization in the rat brain. We rule out the hypothesis that SCxs assembly is disrupted by Aβ accumulation early in the pathology. And we suggest that the decreased activity of SC1 (I+III2+IIn) should be the cause of the brain bioenergetic failure reported in this model.