Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 1/2010

01-01-2010 | Article

Diabetes regulates mitochondrial biogenesis and fission in mouse neurons

Authors: J. L. Edwards, A. Quattrini, S. I. Lentz, C. Figueroa-Romero, F. Cerri, C. Backus, Y. Hong, E. L. Feldman

Published in: Diabetologia | Issue 1/2010

Login to get access

Abstract

Aims/hypothesis

Normal mitochondrial activity is a critical component of neuronal metabolism and function. Disruption of mitochondrial activity by altered mitochondrial fission and fusion is the root cause of both neurodegenerative disorders and Charcot–Marie–Tooth type 2A inherited neuropathy. This study addressed the role of mitochondrial fission in the pathogenesis of diabetic neuropathy.

Methods

Mitochondrial biogenesis and fission were assayed in both in vivo and in vitro models of diabetic neuropathy. Gene, protein, mitochondrial DNA and ultrastructural analyses were used to assess mitochondrial biogenesis and fission.

Results

There was greater mitochondrial biogenesis in dorsal root ganglion neurons from diabetic compared with non-diabetic mice. An essential step in mitochondrial biogenesis is mitochondrial fission, regulated by the mitochondrial fission protein dynamin-related protein 1 (DRP1). Evaluation of diabetic neurons in vivo indicated small, fragmented mitochondria, suggesting increased fission. In vitro studies revealed that short-term hyperglycaemic exposure increased levels of DRP1 protein. The influence of hyperglycaemia-mediated mitochondrial fission on cell viability was evaluated by knockdown of Drp1 (also known as Dnm1l). Knockdown of Drp1 resulted in decreased susceptibility to hyperglycaemic damage.

Conclusions/interpretation

We propose that: (1) mitochondria undergo biogenesis in response to hyperglycaemia, but the increased biogenesis is insufficient to accommodate the metabolic load; (2) hyperglycaemia causes an excess of mitochondrial fission, creating small, damaged mitochondria; and (3) reduction of aberrant mitochondrial fission increases neuronal survival and indicates an important role for the fission–fusion equilibrium in the pathogenesis of diabetic neuropathy.
Appendix
Available only for authorised users
Literature
1.
Leinninger GM, Backus C, Sastry AM, Yi YB, Wang CW, Feldman EL (2006) Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol Dis 23:11–22CrossRefPubMed
2.
Cartoni R, Martinou JC (2009) Role of mitofusin 2 mutations in the physiopathology of Charcot-Marie-Tooth disease type 2A. Exp Neurol 218:268–273CrossRefPubMed
3.
Martin CL, Albers J, Herman WH et al (2006) Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care 29:340–344CrossRefPubMed
4.
Vincent AM, McLean LL, Backus C, Feldman EL (2005) Short-term hyperglycemia produces oxidative damage and apoptosis in neurons. FASEB J 19:638–640PubMed
5.
Huang TJ, Price SA, Chilton L et al (2003) Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of type 1 diabetic rats in the presence of sustained hyperglycemia. Diabetes 52:2129–2136CrossRefPubMed
6.
Vincent AM, Stevens MJ, Backus C, McLean LL, Feldman EL (2005) Cell culture modeling to test therapies against hyperglycemia-mediated oxidative stress and injury. Antioxid Redox Signal 7:1494–1506CrossRefPubMed
7.
Russell JW, Golovoy D, Vincent AM et al (2002) High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16:1738–1748CrossRefPubMed
8.
Berman SB, Pineda FJ, Hardwick JM (2008) Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ 15:1147–1152CrossRefPubMed
9.
Tatsuta T, Langer T (2008) Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 27:306–314CrossRefPubMed
10.
Rasbach KA, Schnellmann RG (2007) Signaling of mitochondrial biogenesis following oxidant injury. J Biol Chem 282:2355–2362CrossRefPubMed
11.
Lopez-Lluch G, Hunt N, Jones B et al (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 103:1768–1773CrossRefPubMed
12.
Cohen HY, Miller C, Bitterman KJ et al (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390–392CrossRefPubMed
13.
St-Pierre J, Drori S, Uldry M et al (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408CrossRefPubMed
14.
Li H, Chen Y, Jones AF et al (2008) Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 105:2169–2174CrossRefPubMed
15.
Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (1998) A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 143:351–358CrossRefPubMed
16.
Zhu PP, Patterson A, Stadler J, Seeburg DP, Sheng M, Blackstone C (2004) Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1. J Biol Chem 279:35967–35974CrossRefPubMed
17.
James DI, Parone PA, Mattenberger Y, Martinou JC (2003) hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 278:36373–36379CrossRefPubMed
18.
Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011CrossRefPubMed
19.
Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409–5420CrossRefPubMed
20.
Sullivan KA, Hayes JM, Wiggin TD et al (2007) Mouse models of diabetic neuropathy. Neurobiol Dis 28:276–285CrossRefPubMed
21.
Mayfield J (1998) Diagnosis and classification of diabetes mellitus: new criteria. Am Fam Physician 58:1355–1370PubMed
22.
Sullivan KA, Lillie JH, Greene DA (1996) Digital electron microscopic analysis of regenerating axon clusters in human sural nerve biopsies. Soc Neurosci Abstr 24:17–37
23.
Kim B, Leventhal PS, Saltiel AR, Feldman EL (1997) Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires MAP kinase activation. J Biol Chem 272:21268–21273CrossRefPubMed
24.
Kim B, Oh SS, van Golen CM, Feldman EL (2004) Differential regulation of insulin receptor substrate-1 degradation during mannitol and okadaic acid induced apoptosis in human neuroblastoma cells. Cell Signal 17:769–775CrossRefPubMed
25.
Vincent AM, Russell JW, Low P, Feldman EL (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25:612–628CrossRefPubMed
26.
Wiggin TD, Kretzler M, Pennathur S, Sullivan KA, Brosius FC, Feldman EL (2008) Rosiglitazone treatment reduces diabetic neuropathy in STZ treated DBA/2 J mice. Endocrinology 149:4928–4937CrossRefPubMed
27.
Howarth FC, Jacobson M, Shafiullah M, Adeghate E (2005) Long-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol 90:827–835CrossRefPubMed
28.
Sullivan KA, Lentz SI, Roberts JL Jr, Feldman EL (2008) Criteria for creating and assessing mouse models of diabetic neuropathy. Curr Drug Targets 9:3–13CrossRefPubMed
29.
Mattingly KA, Ivanova MM, Riggs KA, Wickramasinghe NS, Barch MJ, Klinge CM (2008) Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. Mol Endocrinol 22:609–622CrossRefPubMed
30.
Lelliott CJ, Ljungberg A, Ahnmark A et al (2007) Hepatic PGC-1beta overexpression induces combined hyperlipidemia and modulates the response to PPARalpha activation. Arterioscler Thromb Vasc Biol 27:2707–2713CrossRefPubMed
31.
Sun MG, Williams J, Munoz-Pinedo C et al (2007) Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis. Nat Cell Biol 9:1057–1065CrossRefPubMed
32.
Frank S, Gaume B, Bergmann-Leitner ES et al (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525CrossRefPubMed
33.
Karbowski M, Lee YJ, Gaume B et al (2002) Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159:931–938CrossRefPubMed
34.
Cassidy-Stone A, Chipuk JE, Ingerman E et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204CrossRefPubMed
35.
Powelka AM, Seth A, Virbasius JV et al (2006) Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J Clin Invest 116:125–136CrossRefPubMed
36.
Haden DW, Suliman HB, Carraway MS et al (2007) Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am J Respir Crit Care Med 176:768–777CrossRefPubMed
37.
Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR (2005) Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90:6650–6656CrossRefPubMed
38.
Ghosh S, Patel N, Rahn D et al (2007) The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol 71:1695–1702CrossRefPubMed
39.
Kukidome D, Nishikawa T, Sonoda K et al (2006) Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55:120–127CrossRefPubMed
40.
Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887CrossRefPubMed
41.
Tinari A, Garofalo T, Sorice M, Esposti MD, Malorni W (2007) Mitoptosis: different pathways for mitochondrial execution. Autophagy 3:282–284PubMed
42.
James AM, Murphy MP (2002) How mitochondrial damage affects cell function. J Biomed Sci 9:475–487CrossRefPubMed
43.
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820CrossRefPubMed
44.
Lee HC, Wei YH (2005) Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 37:822–834CrossRefPubMed
45.
Wang X, Su B, Lee HG et al (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci 29:9090–9103CrossRefPubMed
46.
Alexander C, Votruba M, Pesch UE et al (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26:211–215CrossRefPubMed
47.
Bette S, Schlaszus H, Wissinger B, Meyermann R, Mittelbronn M (2005) OPA1, associated with autosomal dominant optic atrophy, is widely expressed in the human brain. Acta Neuropathol 109:393–399CrossRefPubMed
48.
Santel A, Frank S (2008) Shaping mitochondria: the complex posttranslational regulation of the mitochondrial fission protein DRP1. IUBMB Life 60:448–455CrossRefPubMed
49.
Uo T, Dworzak J, Kinoshita C et al (2009) Drp1 levels constitutively regulate mitochondrial dynamics and cell survival in cortical neurons. Exp Neurol 218:274–285CrossRefPubMed
50.
Figueroa-Romero C, Iniguez-Lluhi JA, Standler J et al (2009) SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites with the B domain and is linked to its activity cycle. FASEB J. doi:10.​1096/​fj.​09-136630 PubMed
Metadata
Title
Diabetes regulates mitochondrial biogenesis and fission in mouse neurons
Authors
J. L. Edwards
A. Quattrini
S. I. Lentz
C. Figueroa-Romero
F. Cerri
C. Backus
Y. Hong
E. L. Feldman
Publication date
01-01-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 1/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1553-y

Other articles of this Issue 1/2010

Diabetologia 1/2010 Go to the issue

Article

OVO homologue-like 1 (Ovol1) transcription factor: a novel target of neurogenin-3 in rodent pancreas

Article

HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study

Article

The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice

Article

Cell division autoantigen 1 plays a profibrotic role by modulating downstream signalling of TGF-β in a murine diabetic model of atherosclerosis

Short Communication

The interferon-induced helicase IFIH1 Ala946Thr polymorphism is associated with type 1 diabetes in both the high-incidence Finnish and the medium-incidence Hungarian populations

Review

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits