Mislocalization of neuronal mitochondria reveals regulation of wallerian degeneration and NMNAT/ WLDS-mediated axon protection independent of axonal mitochondria

Brandon M. Kitay, Ryan McCormack, Yunfang Wang, Pantelis Tsoulfas, Rong G Zhai

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Axon degeneration is a common and often early feature of neurodegeneration that correlates with the clinical manifestations and progression of neurological disease. Nicotinamide mononucleotide adenylytransferase (NMNAT) is a neuroprotective factor that delays axon degeneration following injury and in models of neurodegenerative diseases suggesting a converging molecular pathway of axon self-destruction. The underlying mechanisms have been under intense investigation and recent reports suggest a central role for axonal mitochondria in both degeneration and NMNAT/WLDS (Wallerian degeneration slow)-mediated protection. We used dorsal root ganglia (DRG) explants and Drosophila larval motor neurons (MNs) as models to address the role of mitochondria in Wallerian degeneration (WD). We find that expression of Drosophila NMNAT delays WD in human DRG neurons demonstrating evolutionary conservation of NMNAT function. Morphological comparison of mitochondria from WLDS-protected axons demonstrates that mitochondria shrink post-axotomy, though analysis of complex IV activity suggests that they retain their functional capacity despite this morphological change. To determine whether mitochondria are a critical site of regulation for WD, we genetically ablated mitochondria from Drosophila MN axons via the mitochondria trafficking protein milton. Milton loss-of-function did not induce axon degeneration in Drosophila larval MNs, and when axotomized WD proceeded stereotypically in milton distal axons although with a mild, but significant delay. Remarkably, the protective effects of NMNAT/WLDS were also maintained in axons devoid of mitochondria. These experiments unveil an axon self-destruction cascade governing WD that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLDS-mediated axon protection.

Original languageEnglish
Pages (from-to)1601-1614
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number8
DOIs
StatePublished - Apr 1 2013

Fingerprint

Nicotinamide Mononucleotide
Wallerian Degeneration
Axons
Mitochondria
Drosophila
Motor Neurons
Spinal Ganglia
Axotomy
Protein Transport
Neurologic Manifestations
Neurodegenerative Diseases
Disease Progression

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Mislocalization of neuronal mitochondria reveals regulation of wallerian degeneration and NMNAT/ WLDS-mediated axon protection independent of axonal mitochondria. / Kitay, Brandon M.; McCormack, Ryan; Wang, Yunfang; Tsoulfas, Pantelis; Zhai, Rong G.

In: Human Molecular Genetics, Vol. 22, No. 8, 01.04.2013, p. 1601-1614.

Research output: Contribution to journalArticle

@article{49a093878bb5478b9b6cac5dfc93a110,
title = "Mislocalization of neuronal mitochondria reveals regulation of wallerian degeneration and NMNAT/ WLDS-mediated axon protection independent of axonal mitochondria",
abstract = "Axon degeneration is a common and often early feature of neurodegeneration that correlates with the clinical manifestations and progression of neurological disease. Nicotinamide mononucleotide adenylytransferase (NMNAT) is a neuroprotective factor that delays axon degeneration following injury and in models of neurodegenerative diseases suggesting a converging molecular pathway of axon self-destruction. The underlying mechanisms have been under intense investigation and recent reports suggest a central role for axonal mitochondria in both degeneration and NMNAT/WLDS (Wallerian degeneration slow)-mediated protection. We used dorsal root ganglia (DRG) explants and Drosophila larval motor neurons (MNs) as models to address the role of mitochondria in Wallerian degeneration (WD). We find that expression of Drosophila NMNAT delays WD in human DRG neurons demonstrating evolutionary conservation of NMNAT function. Morphological comparison of mitochondria from WLDS-protected axons demonstrates that mitochondria shrink post-axotomy, though analysis of complex IV activity suggests that they retain their functional capacity despite this morphological change. To determine whether mitochondria are a critical site of regulation for WD, we genetically ablated mitochondria from Drosophila MN axons via the mitochondria trafficking protein milton. Milton loss-of-function did not induce axon degeneration in Drosophila larval MNs, and when axotomized WD proceeded stereotypically in milton distal axons although with a mild, but significant delay. Remarkably, the protective effects of NMNAT/WLDS were also maintained in axons devoid of mitochondria. These experiments unveil an axon self-destruction cascade governing WD that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLDS-mediated axon protection.",
author = "Kitay, {Brandon M.} and Ryan McCormack and Yunfang Wang and Pantelis Tsoulfas and Zhai, {Rong G}",
year = "2013",
month = "4",
day = "1",
doi = "10.1093/hmg/ddt009",
language = "English",
volume = "22",
pages = "1601--1614",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "8",

}

TY - JOUR

T1 - Mislocalization of neuronal mitochondria reveals regulation of wallerian degeneration and NMNAT/ WLDS-mediated axon protection independent of axonal mitochondria

AU - Kitay, Brandon M.

AU - McCormack, Ryan

AU - Wang, Yunfang

AU - Tsoulfas, Pantelis

AU - Zhai, Rong G

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Axon degeneration is a common and often early feature of neurodegeneration that correlates with the clinical manifestations and progression of neurological disease. Nicotinamide mononucleotide adenylytransferase (NMNAT) is a neuroprotective factor that delays axon degeneration following injury and in models of neurodegenerative diseases suggesting a converging molecular pathway of axon self-destruction. The underlying mechanisms have been under intense investigation and recent reports suggest a central role for axonal mitochondria in both degeneration and NMNAT/WLDS (Wallerian degeneration slow)-mediated protection. We used dorsal root ganglia (DRG) explants and Drosophila larval motor neurons (MNs) as models to address the role of mitochondria in Wallerian degeneration (WD). We find that expression of Drosophila NMNAT delays WD in human DRG neurons demonstrating evolutionary conservation of NMNAT function. Morphological comparison of mitochondria from WLDS-protected axons demonstrates that mitochondria shrink post-axotomy, though analysis of complex IV activity suggests that they retain their functional capacity despite this morphological change. To determine whether mitochondria are a critical site of regulation for WD, we genetically ablated mitochondria from Drosophila MN axons via the mitochondria trafficking protein milton. Milton loss-of-function did not induce axon degeneration in Drosophila larval MNs, and when axotomized WD proceeded stereotypically in milton distal axons although with a mild, but significant delay. Remarkably, the protective effects of NMNAT/WLDS were also maintained in axons devoid of mitochondria. These experiments unveil an axon self-destruction cascade governing WD that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLDS-mediated axon protection.

AB - Axon degeneration is a common and often early feature of neurodegeneration that correlates with the clinical manifestations and progression of neurological disease. Nicotinamide mononucleotide adenylytransferase (NMNAT) is a neuroprotective factor that delays axon degeneration following injury and in models of neurodegenerative diseases suggesting a converging molecular pathway of axon self-destruction. The underlying mechanisms have been under intense investigation and recent reports suggest a central role for axonal mitochondria in both degeneration and NMNAT/WLDS (Wallerian degeneration slow)-mediated protection. We used dorsal root ganglia (DRG) explants and Drosophila larval motor neurons (MNs) as models to address the role of mitochondria in Wallerian degeneration (WD). We find that expression of Drosophila NMNAT delays WD in human DRG neurons demonstrating evolutionary conservation of NMNAT function. Morphological comparison of mitochondria from WLDS-protected axons demonstrates that mitochondria shrink post-axotomy, though analysis of complex IV activity suggests that they retain their functional capacity despite this morphological change. To determine whether mitochondria are a critical site of regulation for WD, we genetically ablated mitochondria from Drosophila MN axons via the mitochondria trafficking protein milton. Milton loss-of-function did not induce axon degeneration in Drosophila larval MNs, and when axotomized WD proceeded stereotypically in milton distal axons although with a mild, but significant delay. Remarkably, the protective effects of NMNAT/WLDS were also maintained in axons devoid of mitochondria. These experiments unveil an axon self-destruction cascade governing WD that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLDS-mediated axon protection.

UR - http://www.scopus.com/inward/record.url?scp=84875782373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875782373&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddt009

DO - 10.1093/hmg/ddt009

M3 - Article

VL - 22

SP - 1601

EP - 1614

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 8

ER -