ABSTRACT
A decline in the activities of oxidative phosphorylation (OXPHOS) complexes has been consistently reported in amyotrophic lateral sclerosis (ALS) patients and animal models of ALS, although the underlying molecular mechanisms are still elusive. Here, we report that receptor expression enhancing protein 1 (REEP1) acts as an important regulator of complex IV assembly, which is pivotal to preserving motor neurons in SOD1G93A mice. We found the expression of REEP1 was greatly reduced in transgenic SOD1G93A mice with ALS. Moreover, forced expression of REEP1 in the spinal cord extended the lifespan, decelerated symptom progression, and improved the motor performance of SOD1G93A mice. The neuromuscular synaptic loss, gliosis, and even motor neuron loss in SOD1G93A mice were alleviated by increased REEP1 through augmentation of mitochondrial function. Mechanistically, REEP1 associates with NDUFA4, and plays an important role in preserving the integrity of mitochondrial complex IV. Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.
Subject(s)
Mice , Animals , Amyotrophic Lateral Sclerosis/metabolism , Superoxide Dismutase-1/metabolism , Superoxide Dismutase/metabolism , Mice, Transgenic , Spinal Cord/pathology , Mitochondria/physiology , Disease Models, AnimalABSTRACT
Abstract Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. It is genetically heterogeneous, causative mutations have been disclosed in mitochondrial DNA and nuclear genes involved in the process of energy production in the mitochondria .We investigated the whole mitochondrial DNA in three Brazilian patients with LS, based on their clinical and biochemical data, with the aim to identify the disease-causing mutations. In two of the patients, with complex I deficiency, a novel heteroplasmic variant m.4142G>T (p.R279L) in MT-ND1 and a recurrent homoplasmic mutation m.10197G>A (p.A47T) in MT-ND3 were identified. In the remaining patient, with complex IV deficiency, a de novo heteroplasmic variant in MT-CO1 m.6547T>C (p.L215P) was found. The molecular investigation in mitochondrial diseases have shifted their focus from mitochondrial DNA to nuclear DNA, however, mtDNA protein-coding genes are one of the important genetic causes of mitochondrial disorders for Leigh syndrome. This study expands the molecular and clinical spectrum associated with this disease.
ABSTRACT
Objective: To observe the effect of electroacupuncture (EA) on cytochrome c oxidase (COX)activity of hippocampal mitochondria in senescence-accelerated mouse prone 8 (SAMP8) mice, and to explore the EA mechanism on Alzheimer disease (AD) in improving energy metabolic disorder. Methods: Twelve SAMP8 mice were randomly divided into a model group and an EA group, with six in each group. Six senescence-accelerated mouse resistance 1 (SAMR1) mice were prepared as blank group. Mice in the EA group received EA on Baihui (GV 20) and Yongquan (KI 1), once a day for 7 d as a course, altogether 3 courses with one day intervalbetween two courses. Mice in the model group and the blank group were manipulated and fixed as those in the EA group. After interventions, Morris water maze was employed to test spatial learning and memory ability to evaluate EA effect; spectrophotometry was used to detect the activity of hippocampal mitochondria COX. Results: Compared with the blank group, mean escape latenciesof the EA group and model group were prolonged significantly in Morris water maze tests (P Conclusion: It’s plausible that EA improves AD learning and memory ability by increasing mitochondria COX activity, protecting the structure and function, and improving energy metabolism.
ABSTRACT
BACKGROUND:How to control functional activity of donor liver after cardiac death and maintain the optimal function of grafts are the key issues in organ transplantation study. OBJECTIVE:To preliminarily explore the effect of warm ischemia injury on the morphology and function of rat donor liver after cardiac death. METHODS:Cardiac death model was established in Sprague-Dawley rats and the successful models were divided into six groups:control group (warm ischemia for 0 minute), warm ischemia 10 group (warm ischemia for 10 minutes), warm ischemia 20 group (warm ischemia for 20 minutes), warm ischemia 30 group (warm ischemia for 30 minutes), warm ischemia 40 group (warm ischemia for 40 minutes) and warm ischemia 50 group (warm ischemia for 50 minutes). The rat liver specimens in each group were cut into ultrathin sections. The structure of liver cells was observed and photographed by electron microscopy. Flameng score was applied to analyze the degree of mitochondrial damage. Liver mitochondria were extracted and then spectrophotometry was used to assess the viability of cytochrome C oxidase. RESULTS AND CONCLUSION:Under electron microscopy, there were no significant changes in liver cells within 30 minutes of warm ischemia, nuclear membrane was intact, mitochondria mildly swel ed, no mitochondrial crista ruptured, and Flameng score was<2 points. With the extension of warm ischemia time, the cells became swel ing, nuclear chromatin condensated, apoptotic body was clearly visible, mitochondrial matrix coagulated, mitochondria exhibited vacuolation, and Flameng score was 3-4 points. The viability of cytochrome C oxidase showed no significant difference within 30 minutes of warm ischemia, but began to significantly decrease at 40 and 50 minutes. The mitochondrial structure and function after liver injury is not obviously affected by 30 minutes of warm ischemia, and significant changes appear after 40 minutes.
ABSTRACT
BACKGROUND: Mitochondrial dysfunction plays an important role in Abeta-induced neuronal toxicity in Alzheimer's disease (AD). We measured the membrane potentials of mitochondria (delta psim) and assessed the genetic expressions of A beta(25-35)-induced neurotoxicity in the human neuroblastoma cell line, SK-N-SH cell. METHODS: SK-N-SH cells were incubated with a single dose of 25 micrometer A beta(25-35) for 0-24 hours, and kinetic study was done. delta psim was measured by flow cytometry. Messenger RNA expressions of cytochrome c oxidase (COX), cytochrome c, succinate dehydrogenase (SDH), amyloid-beta alcohol dehydrogenase (ABAD), caspase 9, and Bcl-2 were measured by quantitative real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR). Cell death rate was measured by MTT reduction assay. RESULTS: delta psim was reduced at 24 hours. mRNA expression for COX gradually decreased by about 29% (p<0.05) while-expressions for cytochrome c, SDH, ABAD, and caspase 9 increased (p<0.05) progressively during the 24-hour time period. Bcl-2 expression decreased (p<0.05) gradually; and apoptotic cell death rate was about 24% (p<0.01) by 24 hours. CONCLUSION: Extracellular administration of A beta(25-35) contributes directly to mitochondrial dysfunction in SK-N-SH cells with the enzymatic impairment of the tricarboxylic acid cycle and electron transport chain, and eventually leading to apoptotic cell death.