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EBioMedicine. 2015 Apr 11;2(6):499-512. doi: 10.1016/j.ebiom.2015.04.002. eCollection 2015 Jun.

Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy.

Author information

1
Diabetes Research Group, Division of Diabetes and Nutritional Science, Faculty of Life Sciences and Medicine, King's College London, SE1 1UL, UK.
2
Cardiovascular Division.
3
Department of Primary Care and Public Health Sciences.

Abstract

The purpose of this study was to determine if mitochondrial dysfunction plays a role in diabetic nephropathy (DN), a kidney disease which affects > 100 million people worldwide and is a leading cause of renal failure despite therapy. A cross-sectional study comparing DN with diabetes patients without kidney disease (DC) and healthy controls (HCs); and renal mesangial cells (HMCs) grown in normal and high glucose, was carried out. Patients with diabetes (DC) had increased circulating mitochondrial DNA (MtDNA), and HMCs increased their MtDNA within 24 h of hyperglycaemia. The increased MtDNA content in DCs and HMCs was not functional as transcription was unaltered/down-regulated, and MtDNA damage was present. MtDNA was increased in DC compared to HC, conversely, patients with DN had lower MtDNA than DC. Hyperglycaemic HMCs had fragmented mitochondria and TLR9 pathway activation, and in diabetic patients, mitophagy was reduced. Despite MtDNA content and integrity changing within 4 days, hyperglycaemic HMCs had a normal bio-energetic profile until 8 days, after which mitochondrial metabolism was progressively impaired. Peripheral blood mononuclear cells (PBMCs) from DN patients had reduced reserve capacity and maximal respiration, loss of metabolic flexibility and reduced Bioenergetic Health Index (BHI) compared to DC. Our data show that MtDNA changes precede bioenergetic dysfunction and that patients with DN have impaired mitochondrial metabolism compared to DC, leading us to propose that systemic mitochondrial dysfunction initiated by glucose induced MtDNA damage may be involved in the development of DN. Longitudinal studies are needed to define a potential cause-effect relationship between changes in MtDNA and bioenergetics in DN.

KEYWORDS:

Bioenergetic deficit; Bioenergetic health index (BHI); Diabetic nephropathy; Hyperglycemia; Mitochondrial DNA; Mitochondrial dysfunction

PMID:
26288815
PMCID:
PMC4534759
DOI:
10.1016/j.ebiom.2015.04.002
[Indexed for MEDLINE]
Free PMC Article

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