Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.

Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.

Mediterranean diet and psychological well-being intervention to reverse metabolic syndrome in Chile (CHILEMED trial).

Psychosocial status and lifestyle are key risk factors of non-communicable diseases (NCDs), which, in turn, are main drivers of healthcare costs and morbimortality worldwide, including Chile. Mediterranean diet (MedDiet) is one of the healthiest dietary patterns under study. However, its impact on high-risk conditions, such as metabolic syndrome (MetS), and NCDs outside the Mediterranean Basin remains mostly unexplored. Even though Central Chile has an environment, food production, and culinary traditions comparable to those present in Mediterranean countries, few studies -some with significant methodological limitations- have evaluated the effect of MedDiet on health and/or disease in Chilean subjects. Importantly, a Mediterranean lifestyle is a modus vivendi that integrates physical health with mental and social well-being. Psychological well-being (PWB) is associated with healthy behaviors, positive health outcomes, and longevity, thereby emerging as a novel healthcare goal. We report here an ongoing randomized controlled clinical trial in Chilean patients with MetS seeking to test whether (1) a PWB theory-based intervention facilitates induction to and increases long-term adherence to a locally adapted MedDiet, and (2) a MedDiet intervention -implemented alone or combined with well-being promotion- is more effective at reversing MetS compared to individuals following a low-fat diet without psychological support. The CHILEan MEDiterranean (CHILEMED) diet intervention study is a 1-year trial including patients with MetS living in Chile. Participants will be assigned randomly by a computer-generated random number sequence to one of the three intervention arms: a) low-fat diet as control group, b) MedDiet alone, and c) MedDiet plus well-being support. Patients will be followed-up by individual and/or group online nutritional sessions or phone cal as well as 6- and 12-month in-person re-assessment of medical history, medication use, food intake, PWB, anthropometrics/physical exam, and blood collection for laboratory analysis. The primary outcome of the trial will be the effect of the MedDiet -with or without PWB intervention- on overall reversal of MetS compared to low-fat diet alone. Based on a statistical superiority trial, expected impact, and patient loss, the estimated study sample is 339 subjects (113 individuals per arm in 3 equal-sized groups). Currently, we have enrolled 179 patients, predominantly women, evenly distributed by age (group means ranging from 45.7 to 48,9 years-old), 3/4 are obese with almost all of them showing abdominal obesity, 70% are hypertensive, whereas <10% exhibit diabetes. If findings turn out as expected (e.g., MedDiet -with or without PWB intervention- is better than the low-fat diet for reversion of MetS at 1-year follow-up), CHILEMED will provide further beneficial evidence of the MedDiet on NCD risk conditions beyond the Mediterranean region.

IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice.

Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function.

NOX2 Inhibition Impairs Early Muscle Gene Expression Induced by a Single Exercise Bout.

Reactive oxygen species (ROS) participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2) in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg) or vehicle for 3 days, were swim-exercised for 60 min. Phospho-p47(phox) levels were significantly upregulated by exercise in flexor digitorum brevis (FDB). Moreover, exercise significantly increased NOX2 complex assembly (p47(phox)-gp91(phox) interaction) demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx), citrate synthase (CS), mitochondrial transcription factor A (tfam) and interleukin-6 (IL-I6) in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-κB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p < 0.001). These results were corroborated using gp91-dstat in an in vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise.