MOLECULAR MECHANISMS INVOLVED IN EARLY NEURONAL BIOENERGETIC DYSFUNCTION

HAJNÓCZKY, G.; MARTINO ADAMI PV; CUELLO, C; MORELLI L; CASTAÑO, EM

Simposio; AAIC Satellite Symposium; 2018

Bioenergeticfunction is mainly regulated by communications that mitochondria (Mito) makewith a specialized region of the endoplasmic reticulum (ER). Juxtaposition ismediated by protein structures, covering 5-20% of Mito surface and spanning5?20 nm when connecting to smooth ER. Neuronal bioenergetic dysfunction hasbeen suggested as an early event and as a cause for synaptic deficiency andcognitive impairment in Alzheimer?s disease (AD). However, the molecularmechanisms underlying this event are poorly characterized. We recently showedin an animal model of early AD, the transgenic McGill-R-Thy1-APP rats (Tg) thathippocampal synaptosomes of 6 month-old animals have a lower capacity toprovide ATP when an extra energy demand is required. This metabolic dysfunctionis associated with cognitive impairment and may be partially explained bydiminished Complex-I enzymatic activity. Experimental evidence using syntheticAβ peptides and cell lines showed increased ER-Mito coupling suggesting that Aβaccumulation upregulates ER-Mito contacts, leading to mitochondrial dysfunctionpossibly through Ca2+ overloading. To address the impact of intracellular Aβ(iAβ) accumulation in ER-Mito coupling we employed hippocampal primary neuronsfrom embryonic Tg rats and wild-type animals. Neurons were transfected withplasmids coding drug-inducible synthetic inter-organellar short (~5 nm) or long(~20 nm) linkers targeting outer Mito membrane and ER, fused to fluorescentproteins (CFP or YFP) that form a FRET pair upon addition of rapamycin. Liveimaging data recorded by multi-colour epifluorescence microcospy revealed thatneurons from Tg rats display ?relaxed? short ER-Mito distances and no changeswere observed using long linkers. These alterations correlate with bioenergeticimpairment and iAβ levels assessed by high-resolution respirometry and ELISAMultiplex, respectively. ER-Mito distance can vary depending on the metabolicneeds of the cell and the presence of stressors. Tighter associations (~10 nm)are likely to better support lipid transfer while some separation (~20 nm) isneeded for Ca2+ delivery. Our results suggest that iAβ accumulationdownregulates ER-Mito coupling altering lipids rather than Ca2+ transport. Thepresent study provides insights into the earliest molecular mechanisms andbiochemical events that may happen in neurons form AD brain, connecting ER-Mitocoupling with specific lipid changes and synaptic bioenergetic deficit