Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy.
Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.
Vincent
Andrea M
AM
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. andreav@umich.edu
Edwards
James L
JL
McLean
Lisa L
LL
Hong
Yu
Y
Cerri
Federica
F
Lopez
Ignazio
I
Quattrini
Angelo
A
Feldman
Eva L
EL
D000367:Age Factors; D000818:Animals; D001369:Axons / Q000473:pathology / Q000648:ultrastructure*; D001786:Blood Glucose / Q000502:physiology; D002478:Cells, Cultured; D003929:Diabetic Neuropathies / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000502:physiology; D010617:Phenanthridines; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
C521281:5-(6'-triphenylphosphoniumhexyl)-5,6-dihydro-6-phenyl-3,8-phenanthridinediammine; D001786:Blood Glucose; D024101:Mitochondrial Proteins; D010617:Phenanthridines; D014157:Transcription Factors; D050994:Voltage-Dependent Anion Channels; D005947:Glucose
Trends Pharmacol Sci. 2009 Jun;30(6):322-9
19446346
Biochem Pharmacol. 2004 Jan 1;67(1):1-15
14667924
Glia. 1996 Aug;17(4):294-306
8856326
Dev Med Child Neurol. 2010 Apr;52(4):328-30
20163430
Antioxid Redox Signal. 2007 Oct;9(10):1659-75
17867931
Diabetes. 2003 Jan;52(1):165-71
12502508
Diabetes. 2009 Oct;58(10):2376-85
19592619
Antioxid Redox Signal. 2008 Feb;10(2):387-93
17961065
J Neurosci. 2009 Jul 15;29(28):9090-103
19605646
FASEB J. 2005 Jan;19(1):43-52
15629894
Invest Ophthalmol Vis Sci. 2006 Apr;47(4):1594-9
16565397
Curr Drug Targets. 2008 Jan;9(1):3-13
18220709
Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1494-506
16356113
Diabetes. 2005 Jun;54(6):1615-25
15919781
Endocrinology. 2007 Feb;148(2):548-58
17095586
Curr Drug Targets. 2008 Jan;9(1):60-7
18220713
Antioxid Redox Signal. 2009 Mar;11(3):425-38
19072199
Cardiovasc Res. 2008 Jul 15;79(2):341-51
18440987
J Neurochem. 2004 Sep;90(6):1281-9
15341512
Stroke. 2008 Nov;39(11):3057-63
18723421
Cell. 2001 Jun 1;105(5):587-97
11389829
Endocr Rev. 2008 May;29(3):351-66
18048763
Diabetes. 2009 Jun;58(6):1356-64
19252136
Acta Neuropathol. 1997 Feb;93(2):118-28
9039458
Am J Hypertens. 2003 Mar;16(3):173-9
12620694
N Engl J Med. 2003 Apr 3;348(14):1365-75
12672865
Dev Neurobiol. 2008 Sep 15;68(11):1348-61
18666204
Nat Rev Neurosci. 2008 Jul;9(7):505-18
18568013
Exp Neurol. 2009 Aug;218(2):268-73
19427854
Mol Neurobiol. 2006 Apr;33(2):113-31
16603792
Curr Diab Rep. 2007 Aug;7(4):257-64
17686400
Diabetes. 2004 Mar;53(3):726-34
14988258
Cell Death Differ. 2007 Mar;14(3):462-71
17053808
FASEB J. 2002 Nov;16(13):1738-48
12409316
FASEB J. 2005 Apr;19(6):638-40
15677696
Nat Clin Pract Neurol. 2007 Jun;3(6):331-40
17549059
Exp Neurol. 2009 Aug;218(2):247-56
19332061
J Neurol Sci. 2007 Jun 15;257(1-2):206-14
17316694
Exp Neurol. 2007 Dec;208(2):216-27
17927981
Diabetologia. 2010 Jan;53(1):160-9
19847394
Neurobiol Dis. 1999 Oct;6(5):347-63
10527803
Neurobiol Dis. 2007 Dec;28(3):276-85
17804249
Annu Rev Cell Dev Biol. 2006;22:79-99
16704336
Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
16025099
Neurobiol Dis. 2006 Jul;23(1):11-22
16684605
J Histochem Cytochem. 2010 Feb;58(2):207-18
19875847
Am J Physiol Cell Physiol. 2007 Feb;292(2):C670-86
17020935
Int J Biochem Cell Biol. 2009 Oct;41(10):2005-14
19379829
Int J Biochem Cell Biol. 2009 Apr;41(4):879-90
18805504