Introduction In many eukaryotes oxidative phosphorylation, occurring via the mitochondrial electron transport chain (ETC), provides the major means of energy production. Complete removal of this capacity often results in premature death. Recent studies using the nematode Caenorhabditis elegans are surprising because they have revealed that disruption of many of the key components of the normal mitochondrial energy-generating machinery do not result in immediate death, rather they often result in greater than 30% extension of adult lifespan. We have collectively referred to such mutants as Mit (mitochondrial) mutants. Understanding how these animals obtain their unexpected life extension forms the major thrust of my group's research efforts.

Mit Mutants The Mit class of long-lived mutants generally contain loss-of-function or reduced-in-function alterations in components of the canonical ETC, and most exhibit a 20-40% increase in mean adult life span. In some instances life extension can be on the order of 300%. Genetic epistasis experiments indicate that almost all of the Mit mutants act independently of the other major pathway known to extend lifespan in worms - the insulin-like daf 2/daf 16 signaling pathway. We study several Mit mutants including: clk-1, isp-1, lrs-2, frh-1 and atp-3. The first three are defined by discrete point mutations while the latter two are generated by feeding RNAi constructs. Disruption of the canonical ETC occurs at different locations in each of these five Mit mutants:

In clk-1 a defective demethoxyubiquinone (DMQ) mono-oxygenase prevents synthesis of 5 hydroxyubiquinone, the penultimate intermediate of ubiquinone (Q) formation, leading to the accumulation of DMQ instead of Q.

The Rieske iron-sulfur protein subunit of complex III is encoded by isp-1. The isp-1(qm150) mutant allele corresponds to a missense point mutation, the result of which is postulated to affect the redox potential of the 2Fe-2S cluster housed in the head region of the ISP-1 protein. This region normally acts to transfer single reducing equivalents within complex III from ubiquinol to cytochrome c₁. It has been postulated that the isp-1(qm150) mutant allele results in fewer electrons moving down this high affinity arm of the Q-cycle and onto cytochrome c.

lrs 2(mg312) was identified in a screen for genetic alterations that increased nematode life span independent of the daf-2/daf-16 pathway. This mutant exhibits a 200% increase in mean adult life span relative to wild-type animals. lrs-2 encodes mitochondrial tRNA synthetase. The lrs-2(mg312) mutant allele is predicted to encode a truncated and inactive version of this protein The mitochondrial genome of C. elegans encodes 12 polypeptides all of which are components of the ETC – specifically, cytochrome b, subunits I-III of cytochrome c oxidase, the a-chain of the Fo ATPase and finally subunits 1-6 and 4L of NADH dehydrogenase. Loss of all these proteins is predicted to occur in lrs-2(mg312).

atp-3 encodes the delta subunit of FoF₁ATP Synthase (complex V). This complex forms part of the major mechanism by which most cells (but not all), manufacture their ATP.

frh-1 encodes frataxin, the gene disrupted in the debilitating neurodegenerative disorder Friedrich's ataxia. Frataxin performs two functions inside mitochondria - Fe storage and Fe delivery to the Fe-S cluster synthesis machinery. Disruption of frataxin results in the disruption of all Fe-S cluster containing proteins in the cell, including complexes I, II and III of the mitochondrial electron transport chain.

Why are Mit Mutants are long-lived? This is a fascinating question and one we have attempted to answer in some detail in two reviews that we recently wrote (Rea, 2005b, Ventura et. al.  2006). Briefly though, several hypotheses for how Mit mutants may attain their extended longevity can be envisaged, including reduction of mitochondrial reactive oxygen species (ROS) production, hormetic activation of protective anti-oxidant responses, induction of non-canonical mitochondrial ETCs, use of alternate metabolic pathways, changes in protein turnover, and/or altered DNA maintenance, among others. The Mit mutants may alternatively be are a heterogeneous group of longevity mutants sharing only the commonality of adopting different metabolic strategies that bypass their compromised mitochondrial function and which fortuitously all optimize the status quo between key mitochondrial parameters and long life. These key mitochondrial parameters presumably include inner membrane potential (Dp), ROS production and the ability to generate sufficient ATP and NADH for biosynthetic purposes. Interestingly, our most recent finding point toward a common central signal and we are actively persuing it.

Very recently, my colleague and collaborator, Dr. Natascia Ventura (University of Rome, Italy), and I formulated a new hypothesis on longevity specification in the Mit mutants  (Ventura et al, 2006a, Ventura and Rea, 2007). In what might turn out to be a significant advance in our understanding of human mitochondrial-associated diseases, we have postulated that specific and saturable compensatory mechanisms act to counter mitochondrial dysfunction in the Mit mutants and that one 'by-product' of these processes is life extension. Furthermore, we have suggested that these same compensatory processes might just be the same ones that initially act to delay the appearance of mitochondrial pathology in human patients until early in their adult life. Together, Dr. Ventura and I are actively pursuing this line of investigation.

Institute for Behavioral Genetics
This page was last modified 24 June, 2007
srea@colorado.edu