Abstract
Leber's hereditary optic neuropathy (LHON) was the first maternally inherited disease to be associated with point mutations in mitochondrial DNA and is now considered the most prevalent mitochondrial disorder. The pathology is characterized by selective loss of ganglion cells in the retina leading to central vision loss and optic atrophy, prevalently in young males. The pathogenic mtDNA point mutations for LHON affect complex I with the double effect of lowering the ATP synthesis driven by complex I substrates and increasing oxidative stress chronically. In this review, we first consider the biochemical changes associated with the proton-translocating NADH-quinone oxidoreductase of mitochondria in cybrid cells carrying the most common LHON mutations. However, the LHON cybrid bioenergetic dysfunction is essentially compensated under normal conditions, i.e. in glucose medium, but is unrevealed by stressful conditions such as growing cybrids in glucose free/galactose medium, which forces cells to rely only on respiratory chain for ATP synthesis. In fact, the second part of this review deals with the investigation of LHON cybrid death pathway in galactose medium. The parallel marked changes in antioxidant enzymes, during the time-course of galactose experiments, also reveal a relevant role played by oxidative stress. The LHON cybrid model sheds light on the complex interplay amongst the different levels of biochemical consequences deriving from complex I mutations in determining neurodegeneration in LHON, and suggests an unsuspected role of bioenergetics in shaping cell death pathways.
| Original language | English |
|---|---|
| Pages (from-to) | 172-179 |
| Number of pages | 8 |
| Journal | Biochimica et Biophysica Acta - Bioenergetics |
| Volume | 1658 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - Jul 23 2004 |
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Keywords
- Apoptosis
- ATP synthesis
- Complex I
- LHON
- Mitochondria
- ROS
ASJC Scopus subject areas
- Biophysics
Cite this
Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy : A model of mitochondrial neurodegeneration. / Carelli, Valerio; Rugolo, Michela; Sgarbi, Gianluca; Ghelli, Anna; Zanna, Claudia; Baracca, Alessandra; Lenaz, Giorgio; Napoli, Eleonora; Martinuzzi, Andrea; Solaini, Giancarlo.
In: Biochimica et Biophysica Acta - Bioenergetics, Vol. 1658, No. 1-2, 23.07.2004, p. 172-179.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy
T2 - A model of mitochondrial neurodegeneration
AU - Carelli, Valerio
AU - Rugolo, Michela
AU - Sgarbi, Gianluca
AU - Ghelli, Anna
AU - Zanna, Claudia
AU - Baracca, Alessandra
AU - Lenaz, Giorgio
AU - Napoli, Eleonora
AU - Martinuzzi, Andrea
AU - Solaini, Giancarlo
PY - 2004/7/23
Y1 - 2004/7/23
N2 - Leber's hereditary optic neuropathy (LHON) was the first maternally inherited disease to be associated with point mutations in mitochondrial DNA and is now considered the most prevalent mitochondrial disorder. The pathology is characterized by selective loss of ganglion cells in the retina leading to central vision loss and optic atrophy, prevalently in young males. The pathogenic mtDNA point mutations for LHON affect complex I with the double effect of lowering the ATP synthesis driven by complex I substrates and increasing oxidative stress chronically. In this review, we first consider the biochemical changes associated with the proton-translocating NADH-quinone oxidoreductase of mitochondria in cybrid cells carrying the most common LHON mutations. However, the LHON cybrid bioenergetic dysfunction is essentially compensated under normal conditions, i.e. in glucose medium, but is unrevealed by stressful conditions such as growing cybrids in glucose free/galactose medium, which forces cells to rely only on respiratory chain for ATP synthesis. In fact, the second part of this review deals with the investigation of LHON cybrid death pathway in galactose medium. The parallel marked changes in antioxidant enzymes, during the time-course of galactose experiments, also reveal a relevant role played by oxidative stress. The LHON cybrid model sheds light on the complex interplay amongst the different levels of biochemical consequences deriving from complex I mutations in determining neurodegeneration in LHON, and suggests an unsuspected role of bioenergetics in shaping cell death pathways.
AB - Leber's hereditary optic neuropathy (LHON) was the first maternally inherited disease to be associated with point mutations in mitochondrial DNA and is now considered the most prevalent mitochondrial disorder. The pathology is characterized by selective loss of ganglion cells in the retina leading to central vision loss and optic atrophy, prevalently in young males. The pathogenic mtDNA point mutations for LHON affect complex I with the double effect of lowering the ATP synthesis driven by complex I substrates and increasing oxidative stress chronically. In this review, we first consider the biochemical changes associated with the proton-translocating NADH-quinone oxidoreductase of mitochondria in cybrid cells carrying the most common LHON mutations. However, the LHON cybrid bioenergetic dysfunction is essentially compensated under normal conditions, i.e. in glucose medium, but is unrevealed by stressful conditions such as growing cybrids in glucose free/galactose medium, which forces cells to rely only on respiratory chain for ATP synthesis. In fact, the second part of this review deals with the investigation of LHON cybrid death pathway in galactose medium. The parallel marked changes in antioxidant enzymes, during the time-course of galactose experiments, also reveal a relevant role played by oxidative stress. The LHON cybrid model sheds light on the complex interplay amongst the different levels of biochemical consequences deriving from complex I mutations in determining neurodegeneration in LHON, and suggests an unsuspected role of bioenergetics in shaping cell death pathways.
KW - Apoptosis
KW - ATP synthesis
KW - Complex I
KW - LHON
KW - Mitochondria
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=3543025191&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3543025191&partnerID=8YFLogxK
U2 - 10.1016/j.bbabio.2004.05.009
DO - 10.1016/j.bbabio.2004.05.009
M3 - Article
VL - 1658
SP - 172
EP - 179
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
SN - 0005-2728
IS - 1-2
ER -