Format

Send to

Choose Destination
See comment in PubMed Commons below
J Mol Cell Cardiol. 2015 Feb;79:212-23. doi: 10.1016/j.yjmcc.2014.11.008. Epub 2014 Nov 22.

Transgenic overexpression of mitofilin attenuates diabetes mellitus-associated cardiac and mitochondria dysfunction.

Author information

1
West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
2
West Virginia University School of Medicine, Department of Surgery, Morgantown, WV 26506, USA.
3
West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA. Electronic address: jhollander@hsc.wvu.edu.

Abstract

Mitofilin, also known as heart muscle protein, is an inner mitochondrial membrane structural protein that plays a central role in maintaining cristae morphology and structure. It is a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex which is important for mitochondrial architecture and cristae morphology. Our laboratory has previously reported alterations in mitochondrial morphology and proteomic make-up during type 1 diabetes mellitus, with mitofilin being significantly down-regulated in interfibrillar mitochondria (IFM). The goal of this study was to investigate whether overexpression of mitofilin can limit mitochondrial disruption associated with the diabetic heart through restoration of mitochondrial morphology and function. A transgenic mouse line overexpressing mitofilin was generated and mice injected intraperitoneally with streptozotocin using a multi low-dose approach. Five weeks following diabetes mellitus onset, cardiac contractile function was assessed. Restoration of ejection fraction and fractional shortening was observed in mitofilin diabetic mice as compared to wild-type controls (P<0.05 for both). Decrements observed in electron transport chain (ETC) complex I, III, IV and V activities, state 3 respiration, lipid peroxidation as well as mitochondria membrane potential in type 1 diabetic IFM were restored in mitofilin diabetic mice (P<0.05 for all). Qualitative analyses of electron micrographs revealed restoration of mitochondrial cristae structure in mitofilin diabetic mice as compared to wild-type controls. Furthermore, measurement of mitochondrial internal complexity using flow cytometry displayed significant reduction in internal complexity in diabetic IFM which was restored in mitofilin diabetic IFM (P<0.05). Taken together these results suggest that transgenic overexpression of mitofilin preserves mitochondrial structure, leading to restoration of mitochondrial function and attenuation of cardiac contractile dysfunction in the diabetic heart.

KEYWORDS:

Diabetes mellitus; Electron transport chain; Mitochondria; Mitofilin

Comment in

PMID:
25463274
PMCID:
PMC4302057
DOI:
10.1016/j.yjmcc.2014.11.008
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center