frh-1;mml-1

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Genetic mutants with frh-1, mml-1 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Diet
NGM
Lifespan (days)
19.6
Lifespan change (compared to wild type)
19.51%
Phenotype
The kinase involved in energy metabolism that we tested (mml-1) affected longevity induced by RNAi-mediated Mit mutants analyzed other than frh-1 RNAi.
Lifespan comparisons
Double mutant frh-1(RNAi);mml-1(ok849) has a lifespan of 19.6 days, while single mutant frh-1(RNAi) has a lifespan of 19.8 days, single mutant mml-1(ok849) has a lifespan of 15.2 days and wild type has a lifespan of 16.4 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Schiavi A et al., 2013, Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans. Exp Gerontol. 48(2):191-201 23247094 Click here to select all mutants from this PubMed ID in the graph
Abstract
Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich's ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner. In this paper we provide further insight into frataxin control of C. elegans longevity by showing that a substantial reduction of frataxin protein expression is required to extend lifespan, affect sensory neurons functionality, remodel lipid metabolism and trigger autophagy. We find that Beclin and p53 genes are required to induce autophagy and concurrently reduce lipid storages and extend animal lifespan in response to frataxin suppression. Reciprocally, frataxin expression modulates autophagy in the absence of p53. Human Friedreich ataxia-derived lymphoblasts also display increased autophagy, indicating an evolutionarily conserved response to reduced frataxin expression. In sum, we demonstrate a causal connection between induction of autophagy and lifespan extension following reduced frataxin expression, thus providing the rationale for investigating autophagy in the pathogenesis and treatment of Friedreich's ataxia and possibly other human mitochondria-associated disorders.

Search genes: frh-1 mml-1

Entrez ID
Symbol
GenAge
Wormbase ID

174002
frh-1
View on GenAge (frh-1)
WBGene00001486

Frataxin, mitochondrial

Locus: CELE_F59G1.7

Wormbase description: frh-1 encodes the C. elegans frataxin ortholog; by homology, FRH-1 is predicted to be a mitochondrial protein required for biogenesis of iron-sulfur clusters, co-factors necessary for proper function of electron transport chain proteins; in C. elegans, loss of frh-1 activity via RNAi results in small body size, pale coloration, reduced motility, decreased pharyngeal pumping and defecation, reduced egg-laying and fertility, hypersensitivity to oxidative stress, and altered adult lifespan; an frh-1::gfp promoter fusion is expressed in neurons, the pharynx, gut, spermatheca and body wall muscle; in the pharynx, FRH-1 localizes to the mitochondria.

Entrez ID
Symbol
GenAge
Wormbase ID

176050
mml-1
View on GenAge (mml-1)
WBGene00003378

Myc and Mondo-Like;Protein WBSCR14 homolog

Locus: CELE_T20B12.6

Wormbase description: mml-1 encodes, by alternative splicing, two isoforms of a bHLH-ZIP protein orthologous to human MLX (OMIM:602976), MLXIP (OMIM:608090), and MLXIPL (OMIM:605678, deleted in Williams-Beuren syndrome); MML-1 has five N-terminal Mondo Conserved Regions, an N-terminal nuclear localization sequence, and a C-terminal bHLHZip domain; with MXL-2, MML-1 is probably required for normal migration of ray 1 precursor cells in the male tail and for proper epidermal expression of extracellular matrix component genes; MML-1 is expressed in epidermal cells from 50-100 cell embryos onward, and in intestinal cells at the 4E stage, until adulthood; MML-1 requires MXL-2 for protein stability; MML-1 binds MXL-2 but not MXL-1 in two-hybrid assays; either coexpressed MML-1/MXL-2 or MML-1 alone can activate transcription via CACGTG E-boxes.

Orthologs of frh-1;mml-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Fxn;Mlxip
Mus musculus	Fxn;Mlxipl
Mus musculus	Mlxip;Fxn
Mus musculus	Mlxipl;Fxn

Orthologs of frh-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	fh
Mus musculus	Fxn

Orthologs of mml-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Mlxip
Mus musculus	Mlxipl