Mitochonic Acid 5 Improves Duchenne Muscular Dystrophy and Parkinson’s Disease Model of Caenorhabditis elegans

Abstract

Mitochonic Acid 5 (MA-5) enhances mitochondrial ATP production, restores fibroblasts from mitochondrial disease patients and extends the lifespan of the disease model “Mitomouse”. Additionally, MA-5 interacts with mitofilin and modulates the mitochondrial inner membrane organizing system (MINOS) in mammalian cultured cells. Here, we used the nematode Caenorhabditis elegans to investigate whether MA-5 improves the Duchenne muscular dystrophy (DMD) model. Firstly, we confirmed the efficient penetration of MA-5 in the mitochondria of C. elegans. MA-5 also alleviated symptoms such as movement decline, muscular tone, mitochondrial fragmentation and Ca2+ accumulation of the DMD model. To assess the effect of MA-5 on mitochondria perturbation, we employed a low concentration of rotenone with or without MA-5. MA-5 significantly suppressed rotenone-induced mitochondria reactive oxygen species (ROS) increase, mitochondrial network fragmentation and nuclear destruction in body wall muscles as well as endogenous ATP levels decline. In addition, MA-5 suppressed rotenone-induced degeneration of dopaminergic cephalic (CEP) neurons seen in the Parkinson’s disease (PD) model. Furthermore, the application of MA-5 reduced mitochondrial swelling due to the immt-1 null mutation. These results indicate that MA-5 has broad mitochondrial homing and MINOS stabilizing activity in metazoans and may be a therapeutic agent for these by ameliorating mitochondrial dysfunction in DMD and PD.

Mitochonic acid 5 attenuates age-related neuromuscular dysfunction associated with mitochondrial Ca2+ overload in Caenorhabditis elegans

“…Therefore, we monitored mitochondrial Ca 2+ changes in CEPs in young gravid adults only after treatment with low dose of rotenone (mitochondrial complex I inhibitor). Previous observations revealed that 2 mM-rotenone treatment for 24 h similarly increased CEPs' puncta despite young gravid adults, and MA-5 administration suppress the increase in puncta 9 . We therefore used the same treatment conditions to study whether low-dose rotenone increases mitochondrial calcium levels in CEPs and, if so, whether MA-5 can suppress it.…”

“…On the other hand, MA-5 administration reduced mitochondrial Ca 2+ overload induced by aging and rotenone treatment (Fig. 1,2), as well as dys-1 (eg33) mutation 9 , while maintaining MCU activity. These results clearly demonstrate that MA-5 contributes to the maintenance of mitochondrial homeostasis by inhibiting excessive Ca 2+ accumulation, rather than inhibiting normal Ca 2+ uptake into mitochondria.…”

“…MA-5 stabilizes mitochondrial cristae structures through binding to Mito lin/Mic60 in cultured mammalian cells and facilitates ATP synthetase oligomerization 4 . MA-5 also improves distended cristae in C. elegans immt-1/mito lin mutants 9 . Mito lin/Mic60 depletion led to loss of cristae junctions (CJs) 18 .…”

“…MA-5 also prolongs the survival of the mitochondrial disease model mouse "Mitomouse" 8 . Furthermore, we recently found that MA-5 can suppress the pathophysiology of Duchenne muscular dystrophy (DMD) and Parkinson's disease (PD) in C. elegans model, indicating that MA-5 has a broadly conserved potency against metazoan mitochondria 9 . Therefore, one of the next studies is to evaluate whether MA-5 can slow the progression of aging.…”

Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders

“…Nematodes treated with rotenone displayed loss of dopaminergic neurons, growth and motility defects as well as mitochondrial deficits [ 83 , 84 ]. However, a novel synthesized compound, mitochonic acid 5 (MA-5) derived from plant hormone Indole-3-Acetic Acid (IAA), has been shown to significantly reduce mitochondrial ROS elevation and degeneration of dopaminergic neurons, probably through its interaction with mitofilin as previously shown in mammalian cells [ 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]. Symptoms of PD include motor and non-motor symptoms, such as rest tremor, bradykinesia, rigidity, loss of postural reflexes and depression, and can be mostly traced to the loss of dopaminergic neurons in the substantia nigra, which leads to a reduction in dopamine release [ 79 , 80 ].…”