Complex I and Disease Connections

January 27, 2011

Edited by Roderick Capaldi, D.Phil.

Past issues are available for review in the archives.

Table of Contents

I. Complex I in Cancer

II. Complex I in Brain Diseases

III. Complex I in Diabetes

IV. Assembly and Misassembly of Complex I in Disease

V. Toward Gene Therapy for Complex I Deficiency

VI. The Structure of Complex I Comes More into Focus

I. Complex I in Cancer

There have been two recent papers relating complex I mutations with oncocytic tumors. Porcelli et al. generated homoplasmic transmitochondrial cytoplasmic hybrids that were mutant in the mitochondria-coded MTND1 gene. These cells had altered levels of alpha-ketoglutarate and succinate, the Krebs cycle metabolites that are the main metabolites responsible for HIF1alpha stabilization.

In a separate study, Zimmerman et al. examined a number of rare oncocytomas and found a consistent loss of complex I along with compensatory up-regulation of the other respiratory chain complexes. In half of the cases examined the absence of complex I was due to pathogenic mutations in the mt-encoded subunits of the complex. Therefore, they argue, complex I of the respiratory chain should to be added to the growing list of mitochondrial tumor suppressors

The involvement of Complex I mutations in cancer is further demonstrated in a study of sporadic breast cancer. Czarnecka and colleagues report that 23% of the breast cancers they studied had the 10398G mutation in ND3 compared with 3% of controls. This is the same polymorphism/mutation previously reported to be linked to Parkinsons disease and diabetes.

1. Porcelli AM, et al. The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization. Hum Mol Genet. 19(6):1019-32 (2010)

2. Zimmermann FA, et al. Respiratory chain complex I is a mitochondrial tumor suppressor of oncocytic tumors. Front Biosci (Elite Ed).3:315-25.(2011)

3. Czarnecka AM, et al. Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland. Breast Cancer Res. Treat 121. 511-18 (2010)

II. Complex I in Brain Diseases

The link between Complex I deficiency and various neurological conditions continued to grow in 2010. In one study Marui et al. found a link between polymorphisms in NDUFA5 and autism, while Andreazza et al. identified decreased levels of NDUFS7, decreased levels of Complex I activity, and increased levels of both carbonyls and 3-nitrotyrosine in patients with bipolar disorder (but not depressed or schizophrenic patients).

4. Marui T, et al. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism. Acta Psychiatr Scand.123:118-124.(2011)

5. Andreazza AC, Shao L, Wang JF, Young LT. Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder. Arch Gen Psychiatry;67(12):1254. (2010)

III. Complex I in Diabetes

A comparison of muscle proteins from lean and insulin sensitive individuals with those of obese and insulin insensitive individuals has been reported recently by Lefort et al. This work showed that while NADH- and FADH(2)-linked maximal respiration rates were similar in lean and obese individuals, the rates of pyruvate and palmitoyl-DL-carnitine fueled ROS production were significantly higher in obesity. Mitochondria from obese individuals maintained higher (more negative) extramitochondrial ATP free energy at low metabolic flux, and significantly, there was a lower abundance of complex I subunits along with enzymes involved in the oxidation of branched-chain amino acids (BCAA) and fatty acids (e.g. carnitine palmitoyltransferase 1B) in the diabetes patients.

6. Lefort N, et al. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes. 59:2444-52 (2010)

IV. Assembly and Misassembly of Complex I in Disease

The assembly of complex I remains a hot topic. In one elegant study Perales-Clemente et al. generated mouse cell lines mutated for 3 of the ND subunits of the complex and analyzed the subunits of partial assemblies of the complex. They concluded that there are five different steps within the assembly pathway for complex I at which some mitochondrially encoded subunits are incorporated.

Prehaps the most novel finding of 2010 in terms of assembly of complex I is the separate reports of two European consortia that a protein thought to be a component of fatty acid oxidation, ACAD9, is instead involved in complex I assembly. Nouws et. al. show that ACAD9 bind to complex I assembly factors NDUFAF1 and Ecsit. Further, they and the team of Haack et al. show that ACAD9 mutations result in complex I deficiency, but not in disturbed long-chain fatty acid oxidation.

7. Nouws J et al. Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metab. 12:283-94. (2010)

8. Haack TB, et al. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 12:1131-4. 2010

9. Wang Y, Mohsen AW, Mihalik SJ, Goetzman ES, Vockley J. Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J Biol Chem. ;285:29834-41. 2010

V. Toward Gene Therapy for Complex I Deficiency

For some time there has been interest in rescuing complex I deficiencies by using the yeast alternate NADH dehydrogenase Ndi1. This year saw the concept moved a step closer to a treatment. Yagi and colleagues established a rat model of Lebers Hereditary Optic Neuropathy by injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. They were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. They report that even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects.

10. Marella M, Seo BB, Thomas BB, Matsuno-Yagi A, Yagi T. Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model. PLoS One 5. E11472 (2010)

VI. The Structure of Complex I Comes More into Focus

This year has seen further success toward a detailed structure of complex I. Efremov et al. described a structure for the membrane domain of complex I from Escherichia coli at 3.9 A resolution. The antiporter-like subunits NuoL/M/N were found to each contain 14 conserved transmembrane (TM) helices. Two of them are discontinuous, as in some transporters. Unexpectedly, subunit NuoL also contains a 110-A long amphipathic alpha-helix, spanning almost the entire length of the domain. Further these workers have determined the structure of the entire complex I from Thermus thermophilus at 4.5 A resolution. The L-shaped assembly consists of the alpha-helical model for the membrane domain, with 63 TM helices, and the known structure of the hydrophilic domain. They suggest that the architecture of the complex is a strong clue to the coupling mechanism with the conformational changes at the interface of the two main domains driving the long amphipathic alpha-helix of NuoL in a piston-like motion, tilting nearby discontinuous TM helices, and thereby resulting in proton translocation.

11. Efremov RG, Baradaran R, Sazanov LA. The architecture of respiratory complex I. Nature. May 465:441-5. 2010

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