To Eat or Not to Eat: Neuronal Metabolism, Mitophagy, and Parkinson's Disease

Neurons are exquisitely dependent upon mitochondrial respiration to support energy-demanding functions. Mechanisms that regulate mitochondrial quality control have recently taken center stage in Parkinson's disease research, particularly the selective degradation of mitochondria by autophagy (mitophagy). Unlike other cells, neurons show limited glycolytic potential, and both insufficient and excessive mitophagy have been linked to neurodegeneration. Kinases implicated in regulating mammalian mitophagy include extracellular signal-regulated protein kinases (ERK1/2) and PTEN-induced kinase 1 (PINK1). Increased expression of full-length PINK1 enhances recruitment of parkin to chemically depolarized mitochondria, resulting in rapid mitochondrial clearance in transformed cell lines. As parkin and PINK1 mutations cause autosomal recessive parkinsonism, potential defects in clearing dysfunctional mitochondria may contribute to mitochondrial abnormalities in disease. Given the unique features of metabolic regulation in neurons, however, mechanisms regulating mitochondrial network stability and the threshold for mitophagy are likely to vary from cells that preferentially utilize aerobic glycolysis. Moreover, removal of the entire mitochondrial complement may represent part of a neuronal cell death pathway. Future work utilizing physiological injuries that affect only a subset of mitochondria would help to elucidate whether defective recognition of damaged mitochondria, or alternatively, inability to maintain or generate healthy mitochondria, play the major roles in parkinsonian neurodegeneration. Antioxid. Redox Signal. 14, 1979–1987

Nonalcoholic Fatty Liver Disease: Pathogenesis and Therapeutics from a Mitochondria-Centric Perspective

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS

Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans

Objective. This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans (AN). Methods. A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity, glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatonin were measured. Results. After 12 weeks of treatment with melatonin (3 mg/day), homeostasis model assessment insulin resistance index (HOMA-IR) (8.99 ± 5.10 versus 7.77 ± 5.21, p<0.05) and fasting insulin (37.09 5 ± 20.26 μU/ml versus 32.10 ± 20.29 μU/ml, p<0.05) were significantly decreased. Matsuda index (2.82 ± 1.54 versus 3.74 ± 2.02, p<0.05) was significantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight, body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. Conclusions. It was concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improving insulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095

A novel specific aptamer targets cerebrovascular endothelial cells after ischemic stroke

Abstract Cell specific-targeted therapy (CSTT) for acute ischemic stroke remains underdeveloped. Cerebrovascular endothelial cells (CECs) are key components of the blood–brain barrier and are the first brain cells affected by ischemic stroke. After stroke, CEC injury causes insufficient energy supply to neurons and leads to cytotoxic and vasogenic brain edema. Aptamers are short single-stranded RNA or DNA molecules that can bind to specific ligands for cell specific delivery. The expression of vascular cell adhesion molecule-1 (VCAM-1) is increased on CECs after stroke. Herein, we report that an RNA-based VCAM-1-aptamer can specifically target CECs in stroke brains following transient middle cerebral artery occlusion in mice. Our data demonstrate the potential of an RNA-based aptamer as an effective delivery platform to target CECs after stroke. We believe this method will allow for the development of CSTT for treatment of patients with stroke