title: Mitochondrial DNA haplogroups modify the risk of osteoarthritis by altering mitochondrial function and intracellular mitochondrial signals.
abstract: Haplogroup G predisposes one to an increased risk of osteoarthritis (OA) occurrence, while haplogroup B4 is a protective factor against OA onset. However, the underlying mechanism is not known. Here, by using trans-mitochondrial technology, we demonstrate that the activity levels of mitochondrial respiratory chain complex I and III are higher in G cybrids than in haplogroup B4. Increased mitochondrial oxidative phosphorylation (OXPHOS) promotes mitochondrial-related ATP generation in G cybrids, thereby shifting the ATP generation from glycolysis to OXPHOS. Furthermore, we found that lower glycolysis in G cybrids decreased cell viability under hypoxia (1% O2) compared with B4 cybrids. In contrast, G cybrids have a lower NAD(+)/NADH ratio and less generation of reactive oxygen species (ROS) under both hypoxic (1% O2) and normoxic (20% O2) conditions than B4 cybrids, indicating that mitochondrial-mediated signaling pathways (retrograde signaling) differ between these cybrids. Gene expression profiling of G and B4 cybrids using next-generation sequencing technology showed that 404 of 575 differentially expressed genes (DEGs) between G and B4 cybrids are enriched in 17 pathways, of which 11 pathways participate in OA. Quantitative reverse transcription PCR (qRT-PCR) analyses confirmed that G cybrids had lower glycolysis activity than B4 cybrids. In addition, we confirmed that the rheumatoid arthritis pathway was over-activated in G cybrids, although the remaining 9 pathways were not further tested by qRT-PCR. In conclusion, our findings indicate that mtDNA haplogroup G may increase the risk of OA by shifting the metabolic profile from glycolysis to OXPHOS and by over-activating OA-related signaling pathways.
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: hezhifang990909@gmail.com.
authors.forename: Hezhi
authors.initials: H
authors.lastname: Fang
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Li
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Du
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: You
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Hezhongrong
authors.initials: H
authors.lastname: Nie
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Shen
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: baiy@uthscsa.edu.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: jxlu313@163.com.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lyu
mesh_terms: D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins
keywords: Chondrocyte; Mitochondrial DNA haplogroup; Osteoarthritis; Retrograde signaling