Anales de la RANM

83 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 AMYOTROPHIC LATERAL SCLEROSIS IS NOT ONLY A MOTOR NEURON DISEASE Fernández A, et al. An RANM. 2022;139(01): 78 - 87 Alterations of mitochondria structure and bioenergetic functions are considered to be central stage in the pathogenesis of neurodegen- erative diseases. ALS patient’s postmortem studies revealed structural neurofibrillary alterations with the presence of vacuoles in axons and dendrites; these pathological features were associated to damaged mitochondria (40). Similar alterations were observed in mouse models carrying SOD1 mutations. Mitochondria are the source of cellular energy; they are also implicated in the intracel- lular calcium homeostasis, calcium-mediated excitotoxicity, and in the intrinsic apoptotic pathway (41). All these functions are affected in ALS and thus, mitochondria are being considered central stage in disease pathogenesis; in fact, ALS is currently considered as a secondary mitochon- driopathy (42). In the adrenal CC, mitochondria play a crucial role in the dissipation of the subplasmalemmal high calcium microdomains (HCMDs) that build up during cell stimulation; these are required to trigger fast exocytosis (43). Hence, if mitochon- dria are depolarized, the Ca 2+ uptake into their matrix is blocked; in this manner, the HCMD is not cleared up and the exocytotic response is potentiated (43). In the light of these relevant functions of mitochondria in CCs and the altera- tions undergone by brain mitochondria in ALS, we felt of interest to perform an extensive ultrastruc- tural and functional analysis of mitochondria in CCs of the SOD1 G93A mouse model of ALS, at presymptomatic and symptomatic stages (44). In this study we found the following changes in CCs from SOD1 G93A mice with respect to WT mice (Fig. 4) (i) higher number of mitochondria with smaller size; (ii) accumulation of mutated SOD1 in mitochondria, cytoplasm and nuclei; (iii) formation of mutated SOD1 aggregates; (iv) increased production of free radicals; (v) decreased expression of the gene coding for OPA1; (vi) augmented size of mitochondrial cristae junctions; (vii) diffusion of cristae components and ions towards the intermembrane space; (viii) diffusion of big molecules and proteins such as hSOD1 G93A inside cristae; (ix) loss of mitochon- drial membrane potential (mψ) with deficiency in oxidative phosphorylation (OXPHOS). Of interest is the observation that several of these changes were present at pre-disease 2-month-old SOD1 G93A mice; as phenotypic symptoms appeared (at 3-months-old onwards), the pathological features accumulated and were more visible. Figure 3. Overimpossed averaged secretory spikes in CCs from AD (APP/PS1) and ALS (SOD1G93A) mouse models. (Adap- ted from de Diego and García, 2018). ALTERED STRUCTURE AND FUNCTION OF MITOCHONDRIA IN CHROMAFFIN CELLS OF SOD1G93A MOUSE MODEL