Dataset Information

Clinical, biochemical, and genetic analysis of the mitochondrial respiratory chain complex I deficiency.

ABSTRACT: Mitochondrial respiratory chain complex I deficiency is one of common mitochondrial disorders. However, the information is relatively little about the features of Chinese patients. In this study, the clinical, biological, and genetic analyses were performed in the children with respiratory chain complex I deficiency, in order to further understand the characteristics of the disease.Over a 3-year period, 67 patients (37 boys, 30 girls), presenting with unexplained multisystemic symptoms and signs were recruited. Clinical and laboratory data of the patients were summarized. Spectrophotometric assay was used for the analysis of mitochondrial complex I-V enzyme activity in peripheral leukocytes. The entire mitochondrial DNA (mtDNA) sequence was analysed for patients and their mothers.The children with respiratory chain complex I deficiency presented with multisystem dysfunction. Onset occurred before the third year of life in 96.9% patients without mtDNA mutation. Onset occurred before the third year of life in 76.5% of patients with mtDNA mutation (P?=?.03). About 51.5% of patients without mtDNA mutation had weakness, which is higher than 24% patients with mtDNA mutation (P?=?.02). Isolated complex I deficiency and combined complex I deficiency were found in 45 and 22 patients, respectively. The prevalence of isolated complex I deficiency was higher in the patients with mtDNA mutations (79.4%) than in the patients without mtDNA mutations (54.5%).Patients with nuclear DNA mutations are more likely to develop early onset in mitochondrial respiratory chain complex I deficiency. The patients with complex I deficiency of peripheral leukocytes may be more likely to be caused by mtDNA mutation.

SUBMITTER: Ma YY

PROVIDER: S-EPMC6133606 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Clinical, biochemical, and genetic analysis of the mitochondrial respiratory chain complex I deficiency.

Ma Yan-Yan YY Li Xi-Yuan XY Li Zhi-Qin ZQ Song Ji-Qing JQ Hou Jing J Li Jian-Hua JH Sun Li L Jiang Jun J Yang Yan-Ling YL

Medicine 20180801 32

Mitochondrial respiratory chain complex I deficiency is one of common mitochondrial disorders. However, the information is relatively little about the features of Chinese patients. In this study, the clinical, biological, and genetic analyses were performed in the children with respiratory chain complex I deficiency, in order to further understand the characteristics of the disease.Over a 3-year period, 67 patients (37 boys, 30 girls), presenting with unexplained multisystemic symptoms and signs ...[more]

PMID: 30095618

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Project description:Mitochondria are key organelles for cellular metabolism, and regulate several processes including cell death and macroautophagy/autophagy. Here, we show that mitochondrial respiratory chain (RC) deficiency deactivates AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis) signaling in tissue and in cultured cells. The deactivation of AMPK in RC-deficiency is due to increased expression of the AMPK-inhibiting protein FLCN (folliculin). AMPK is found to be necessary for basal lysosomal function, and AMPK deactivation in RC-deficiency inhibits lysosomal function by decreasing the activity of the lysosomal Ca2+ channel MCOLN1 (mucolipin 1). MCOLN1 is regulated by phosphoinositide kinase PIKFYVE and its product PtdIns(3,5)P2, which is also decreased in RC-deficiency. Notably, reactivation of AMPK, in a PIKFYVE-dependent manner, or of MCOLN1 in RC-deficient cells, restores lysosomal hydrolytic capacity. Building on these data and the literature, we propose that downregulation of the AMPK-PIKFYVE-PtdIns(3,5)P2-MCOLN1 pathway causes lysosomal Ca2+ accumulation and impaired lysosomal catabolism. Besides unveiling a novel role of AMPK in lysosomal function, this study points to the mechanism that links mitochondrial malfunction to impaired lysosomal catabolism, underscoring the importance of AMPK and the complexity of organelle cross-talk in the regulation of cellular homeostasis. Abbreviation: ΔΨm: mitochondrial transmembrane potential; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATP: adenosine triphosphate; ATP6V0A1: ATPase, H+ transporting, lysosomal, V0 subbunit A1; ATP6V1A: ATPase, H+ transporting, lysosomal, V0 subbunit A; BSA: bovine serum albumin; CCCP: carbonyl cyanide-m-chlorophenylhydrazone; CREB1: cAMP response element binding protein 1; CTSD: cathepsin D; CTSF: cathepsin F; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; EBSS: Earl's balanced salt solution; ER: endoplasmic reticulum; FBS: fetal bovine serum; FCCP: carbonyl cyanide-p-trifluoromethoxyphenolhydrazone; GFP: green fluorescent protein; GPN: glycyl-L-phenylalanine 2-naphthylamide; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryonic fibroblast; MITF: melanocyte inducing transcription factor; ML1N*2-GFP: probe used to detect PtdIns(3,5)P2 based on the transmembrane domain of MCOLN1; MTORC1: mechanistic target of rapamycin kinase complex 1; NDUFS4: NADH:ubiquinone oxidoreductase subunit S4; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; pcDNA: plasmid cytomegalovirus promoter DNA; PCR: polymerase chain reaction; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; P/S: penicillin-streptomycin; PVDF: polyvinylidene fluoride; qPCR: quantitative real time polymerase chain reaction; RFP: red fluorescent protein; RNA: ribonucleic acid; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; shRNA: short hairpin RNA; siRNA: small interfering RNA; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TMRM: tetramethylrhodamine, methyl ester, perchlorate; ULK1: unc-51 like autophagy activating kinase 1; ULK2: unc-51 like autophagy activating kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; v-ATPase: vacuolar-type H+-translocating ATPase; WT: wild-type.

Dataset Information

Clinical, biochemical, and genetic analysis of the mitochondrial respiratory chain complex I deficiency.

Publications

Clinical, biochemical, and genetic analysis of the mitochondrial respiratory chain complex I deficiency.

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