NADH Ubiquinone Reductase
A Complex Involved in Many Different Diseases
November 30, 2009
Edited by Roderick Capaldi, D.Phil.
Past issues are available for review in the archives.
Table of Contents
I. INTRODUCTION
II. THE KEY ROLE OF COMPLEX I IN PARKINSON'S DISEASE
III. COMPLEX I AND SCHIZOPHRENIA
IV. COMPLEX I DEFICIENCY IN OTHER NEUROLOICAL DISORDERS
V. POLYMORPHISMS OF MITOCHONDRIALLY–ENCODED SUBUNITS OF COMPLEX I LINK THIS COMPLEX TO OTHER DISORDERS
I. INTRODUCTION
The more we learn about Complex I, the more we realize the importance of this enzyme complex’s efficiency in human health. It is the entry point of electrons from NADH into oxidative phosphorylation as the name implies, and surprisingly, this complex is the determinant of overall throughput because the threshold at which dysfunction affects ATP production is lower than that of any other OXPHOS complexes (around 30% reduction in Complex I activity is sufficient to reduce O2 consumption and ATP synthesis). Most significantly, inhibition of Complex I results in generation and release of reactive oxygen species, which induces collateral damage to cells, thereby amplifying the initial dysfunction of the Complex itself. The breadth of the involvement of Complex I in human diseases has been covered recently in an excellent review and a systems biology study below.
1. Sharma LK, Lu J, Bai Y. Mitochondrial respiratory complex I: structure, function and implication in human diseases. Curr Med Chem. 2009;16(10):1266-77.
2. Pagliarini DJ, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008 Jul 11;134(1):112-23.
II. THE KEY ROLE OF COMPLEX I IN PARKINSON'S DISEASE
The role of mitochondria, and Complex I in particular, in PD is now widely accepted. Several recent papers have extended our understanding about the link between Complex I activity and the disease. A recent review describes much of the recent work in this area.
3. Büeler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol. 2009 Aug;218(2):235-46. Epub 2009 Mar 18.
One novel finding recently is that the interaction of alpha-Synuclein with Complex I affects electron transfer activity by reducing electron transfer rates and increasing free radical production.
4. Liu G, et al. alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci Lett. 2009 May 1;454(3):187-92. Epub 2009 Feb 28.
Much of what we understand about PD comes from studies in humans as well as models in Drosophila, mice, and rats. A relatively new model for studying PD is zebrafish. Recently, Flinn and colleagues induced parkin deficiency in this organism. They found that the parkin gene is expressed throughout zebrafish development and is ubiquitously expressed in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Notably, the authors report that parkin knockdown in zebrafish embryos causes a specific reduction in the activity of the mitochondrial respiratory chain Complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. Complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients.
5. Flinn L, Mortiboys H, Volkmann K, Köster RW, Ingham PW, Bandmann O. Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain. 2009 Jun;132(Pt 6):1613-23. Epub 2009 May 12.
III. COMPLEX I AND SCHIZOPHRENIA
As discussed in a previous issue of MitoNews, hypoxia induces expression of transcription factor HIF-1 which leads to increased expression of PDK1, along with upregulation of glycolytic enzymes. These transcriptional changes increase glucose flux to pyruvate and glycolytic ATP production, and suppress both Krebs cycle and respiration by the PDK1-mediated phosphorylation of PDH, thus causing a metabolic switch from oxidative to glycolytic glucose utilization. Importantly, the HIF-1-dependent block of respiration promotes cell survival.
6. Brenner-Lavie H, Klein E, Ben-Shachar D. Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells. Biochem Pharmacol. 2009 Jul 1;78(1):85-95. Epub 2009 Apr 2.
7. Brenner-Lavie H, Klein E, Zuk R, Gazawi H, Ljubuncic P, Ben-Shachar D. Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia. Biochim Biophys Acta. 2008 Feb;1777(2):173-85. Epub 2007 Oct 23.
IV. COMPLEX I DEFICIENCY IN OTHER NEUROLOICAL DISORDERS
In a recent study of fibroblasts from three patients with Charcot-Marie-Tooth disease caused by the dominant GDAP1 mutation, C240Y (c.719G > A), Complex I activity was 40% lower than in controls, while the tubular mitochondria were 33% larger in diameter and the mitochondrial mass was 20% greater. This leads the authors to suggest that GDAP1 is involved not only in mitochondrial network dynamics, but also in energy production via Complex I.
8. Cassereau J, et al. Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). Neurogenetics. 2009 Apr;10(2):145-50. Epub 2008 Dec 17.
V. POLYMORPHISMS OF MITOCHONDRIALLY–ENCODED SUBUNITS OF COMPLEX I LINK THIS COMPLEX TO OTHER DISORDERS
Polymorphic variations in the subunits of Complex I have been identified in relation to the pathogenesis of several so-called “mitochondrial diseases,” including Leber’s Hereditary Optic Neuropathy and MELAS. Recent studies have described interesting variants in Complex I genes in sepsis, alcoholism, hypertension, and macular degeneration as listed below.
9. Gomez R, O'Keeffe T, Chang LY, Huebinger RM, Minei JP, Barber RC. Association of mitochondrial allele 4216C with increased risk for complicated sepsis and death after traumatic injury. J Trauma. 2009 Mar;66(3):850-7; discussion 857-8.
10. Sapag A, et al. Polymorphisms in mitochondrial genes encoding complex I subunits are maternal factors of voluntary alcohol consumption in the rat. Pharmacogenet Genomics. 2009 Jul;19(7):528-37.
11. Kokaze A, et al. NADH dehydrogenase subunit-2 237 Leu/Met polymorphism modulates the effects of coffee consumption on the risk of hypertension in middle-aged Japanese men. J Epidemiol. 2009;19(5):231-6. Epub 2009 Aug 8.
12. SanGiovanni JP, et al. Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One. 2009;4(5):e5508. Epub 2009 May 12.
From the foregoing, it is clear that the coordination of electron transfer, coupled with proton translocation and the disruption of this coupling to produce reactive oxygen species in and from Complex I, is a function of both genetics and environmental factors, such as toxins and drug treatments. The implication is that the physiological functioning of Complex I can only be described by summation of genetic variations along with the extent of, and variation in, phosphorylation, acetylation, as well as proteolytic modifications of subunits of the Complex by calpains, granzymes and possibly other proteases, and this for a Complex with 45 subunits. To quote a recent song by Coldplay, “nobody said it would be easy, but nobody said it would be this hard” to understand how Complex I responds to cellular stress. Fortunately, it is now possible to immunocapture the active enzyme complex from cells or tissues of different populations and after different treatments. This simple purification of the Complex from small amounts of sample, which can be done while maintaining any induced cellular modifications to the protein, should greatly aid in analyzing the key factors relating structure and enyzmic activity with pathophysiology.
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