Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation

Abstract

Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1G93A-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1G93A, with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.

Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis

“…Also, the neuronal compartment has metabolic defects in the ALS context. In mouse model, both spinal and cortical neurons have hampered basal respiration, maximal respiration, spare capacity and ATP production 69 . This alteration has been linked to defects in the autophagic process and in signaling pathways controlling energy homeostasis 69,70 .…”

“…In mouse model, both spinal and cortical neurons have hampered basal respiration, maximal respiration, spare capacity and ATP production 69 . This alteration has been linked to defects in the autophagic process and in signaling pathways controlling energy homeostasis 69,70 . Adipose tissue has been poorly investigated in ALS; different reports highlight that also white adipose tissue have metabolic defects.…”

“…According to the lipolytic process, in the present work we showed that BAT have lower activation of the lipolytic signaling under control of PKA, while mPBAs are unable to properly respond to the beta-adrenergic stimulation. Importantly, metabolic homeostasis can be rewired both in vitro and in vivo, correlating with amelioration of tissue structure and ultrastructure as well as animal motor symptoms 64,69,71 . Moreover, in our study we presented a characterization of the mitochondrial dynamics in primary pre-adipocytes extracted from BAT of wild type and SOD1-G93A mice.…”