Altered mitochondrial dynamics and response to insulin in cybrid cells harboring a diabetes-susceptible mitochondrial DNA haplogroup.
The advantage of using a cytoplasmic hybrid (cybrid) model to study the genetic effects of mitochondria is that the cells have the same nuclear genomic background. We previously demonstrated the independent role of mitochondria in the pathogenesis of insulin resistance (IR) and pro-inflammation in type 2 diabetes. In this study, we compared mitochondrial dynamics and related physiological functions between cybrid cells harboring diabetes-susceptible (B4) and diabetes-protective (D4) mitochondrial haplogroups, especially the responses before and after insulin stimulation. Cybrid B4 showed a more fragmented mitochondrial network, impaired mitochondrial biogenesis and bioenergetics, increased apoptosis and ineffective mitophagy and a low expression of fusion-related molecules. Upon insulin stimulation, increases in network formation, mitochondrial DNA (mtDNA) content, and ATP production were observed only in cybrid D4. Insulin promoted a pro-fusion dynamic status in both cybrids, but the trend was greater in cybrid D4. In cybrid B4, the imbalance of mitochondrial dynamics and impaired biogenesis and bioenergetics, and increased apoptosis were significantly improved in response to antioxidant treatment. We concluded that diabetes-susceptible mtDNA variants are themselves resistant to insulin.
Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; Department of Neuroscience, Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
Hsiao-Mei
HM
Kuo
Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Shao-Wen
SW
Weng
Institute of Physiology and Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan.
Alice Y W
AY
Chang
Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Hung-Tu
HT
Huang
Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Hung-Yu
HY
Lin
Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Jiin-Haur
JH
Chuang
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Tsu-Kung
TK
Lin
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Chia-Wei
CW
Liou
Department of Biological Sciences, Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Ming-Hong
MH
Tai
Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Ching-Yi
CY
Lin
Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan. Electronic address: wangpw@adm.cgmh.org.tw.
Pei-Wen
PW
Wang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*
D000975:Antioxidants; D004272:DNA, Mitochondrial; D007328:Insulin; D000255:Adenosine Triphosphate
Cybrid; Insulin resistance; Mitochondrial dynamics; Oxidative stress