Mitochondrial complex I: stabilization and activity in a rat model of cerebral amyloidosis.

NOVACK, GISELA V.; GALEANO, PABLO; CASTAÑO EM; CUELLO, A CLAUDIO; MORELLI LAURA

Mar del Plata

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2023

SAIC

Bioenergetic dysfunction has been suggested as an early event and a cause of synaptic and cognitive deficiency in Alzheimer’s Disease (AD). Previous reports showed impairments in mitochondrial Complex I (CI) activity associated to brain amyloidosis, however the molecular basis underlying this disturbance was not deeply established. Here we evaluated in McGill-R-Thy1-APP transgenic (Tg) rat, a model of AD-like cerebral amyloidosis, if there is a time-course dis-organization of CI (a multimeric protein) in Supercomplexes (SCs) and if this process affects CI activity. Mitochondria were isolated from hippocampus of young (3 month) and old (9-12 month) animals (n=3/group) and the organization and abundance of SCs analyzed by electrophoretic runs on native gels. CI functionality was assessed by in-gel activity. T-test was applied for statistical analysis. We found by Western-blot (WB) similar amounts of the individual mitochondrial complexes (CI, CII, CIII, CIV and CV) and no differences in the assembly of SC1 (I+III2), SC2 (I+III2+IV) and SC3 (I2+III2) betweengenotypes. However, a lower CI activity was detected in the aged Tg as compared to young animals. To address if aged-associated impaired CI activity was linked to decrements of its relevant sub-unitswe assessed the expression of NDUFB8 (hydrophobic arm), NDU-FA9 (hinge) and NDUFS2 (catalytic core). Similar levels of NDUFB8 and NDUFS2, and reduced amounts of NDUFA9 were detected in aged Tg vs. WT rats. NDUFA9 is encoded by a nuclear gene and translocates from cytoplasm to mitochondria, therefore we assessedits cytoplasmic levels in both genotypes. We detected higher cytoplasmic amounts of preprotein-NDUFA9 in aged Tg. NDUFA9 is imported to mitochondria after conversion of preprotein to mature one. We speculate that in a setting of high amyloid β levels, the process-ing of NDUFA9 may be impaired precluding its translocation and stabilization of CI, a late step critical for CI biogenesis and activity