Mechanisms of Developmental Delay in the Mitochondrial Longevity Mutants Such as isp-1, a Rieske iron sulphur protein (ISP), in C. elegans

By Gholamali Jafari

Mutations in mitochondrial electron transport chain (ETC) components increase life span of yeast, C. elegans, Drosophila, and mice1-6. In C.elegans, during L3-L4 stage, mitochondria undergo a period of dramatic proliferation7 and it has been shown that L3-L4 stages are critical periods in which compromises in ETC function increase the adult life span4. Reduction of the ETC functions during adulthood does not result in increased longevity. How the mitochondrial signaling pathway modulates the aging process and the identity of the pathway constituents that transmit these longevity signals remain unknown.

It has been shown by other groups8,9 that mutation in a subunit of the mitochondrial complex III, isp-1(qm150), causes all timed physiological rates to be much slower (1.5- to 5-fold) compared with the wild-type (Figure 1., our data). In addition, the rate of aging appears to be slowed down as the mean and maximum lifespan of isp-1(qm150) mutant are dramatically increased. Remarkably, in spite of slow physiological rates phenotypes, these animals appear very healthy and their embryonic and postembryonic lethality remain very low.

isp-1 encodes a Rieske iron sulphur protein (ISP) subunit of the mitochondrial complex III in the mitochondrial membrane (ETC subunits are highly conserved in all aerobic bacteria and eukaryotic mitochondria). Mitochondrial complex III catalyses electron transport from ubiquinol to cytochrome c. isp-1(qm150) mutants show low oxygen consumption, decreased sensitivity to reactive oxygen species, and increased lifespan; suggesting that mitochondrial electron transport is a key factor affecting life span9-11.

My team is dissecting the mechanisms by which ETC dysfunction results in slowing all timed physiological rates. In the first step, we are using EMS/ENU mutagenesis suppressor screen12 to detect the genetic pathways that are involved in the developmental delay in isp-1(qm150). Having success in the mutagenesis suppressor screen, we expand our knowledge in molecular mechanisms that regulate the isp-1(qm150) and other ETC mutants development and lifespan.


 

Figure 1. isp-1(qm150) mutant develops slower than N2(WT).

 

1 Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Current biology : CB 19, 1591-1598, doi:10.1016/j.cub.2009.08.016 (2009).

2 Dell'agnello, C. et al. Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Human molecular genetics 16, 431-444, doi:10.1093/hmg/ddl477 (2007).

3 Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830-834, doi:10.1126/science.1074240 (2002).

4 Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398-2401, doi:10.1126/science.1077780 (2002).

5 Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS genetics 4, e24, doi:10.1371/journal.pgen.0040024 (2008).

6 Lapointe, J., Stepanyan, Z., Bigras, E. & Hekimi, S. Reversal of the mitochondrial phenotype and slow development of oxidative biomarkers of aging in long-lived Mclk1+/- mice. The Journal of biological chemistry 284, 20364-20374, doi:10.1074/jbc.M109.006569 (2009).

7 Tsang, W. Y. & Lemire, B. D. Mitochondrial genome content is regulated during nematode development. Biochemical and biophysical research communications 291, 8-16, doi:10.1006/bbrc.2002.6394 (2002).

8 Rea, S. L., Ventura, N. & Johnson, T. E. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS biology 5, e259, doi:10.1371/journal.pbio.0050259 (2007).

9 Feng, J., Bussiere, F. & Hekimi, S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Developmental cell 1, 633-644 (2001).

10 Marcotte, E. M., Xenarios, I., van Der Bliek, A. M. & Eisenberg, D. Localizing proteins in the cell from their phylogenetic profiles. Proceedings of the National Academy of Sciences of the United States of America 97, 12115-12120, doi:10.1073/pnas.220399497 (2000).

11 Hekimi, S. & Guarente, L. Genetics and the specificity of the aging process. Science 299, 1351-1354, doi:10.1126/science.1082358 (2003).

12 Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71-94 (1974).