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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 191-201 |
| Number of pages | 11 |
| Journal | Experimental Gerontology |
| Volume | 48 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2013 |
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Keywords
- Aging
- Autophagy
- Fat
- Frataxin
- Mitochondria
- Nematode
- P53/cep-1
ASJC Scopus subject areas
- Aging
- Biochemistry
- Cell Biology
- Endocrinology
- Genetics
- Molecular Biology
Cite this
Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans. / Schiavi, Alfonso; Torgovnick, Alessandro; Kell, Alison; Megalou, Evgenia; Castelein, Natascha; Guccini, Ilaria; Marzocchella, Laura; Gelino, Sara; Hansen, Malene; Malisan, Florence; Condò, Ivano; Bei, Roberto; Rea, Shane L.; Braeckman, Bart P.; Tavernarakis, Nektarios; Testi, Roberto; Ventura, Natascia.
In: Experimental Gerontology, Vol. 48, No. 2, 02.2013, p. 191-201.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans
AU - Schiavi, Alfonso
AU - Torgovnick, Alessandro
AU - Kell, Alison
AU - Megalou, Evgenia
AU - Castelein, Natascha
AU - Guccini, Ilaria
AU - Marzocchella, Laura
AU - Gelino, Sara
AU - Hansen, Malene
AU - Malisan, Florence
AU - Condò, Ivano
AU - Bei, Roberto
AU - Rea, Shane L.
AU - Braeckman, Bart P.
AU - Tavernarakis, Nektarios
AU - Testi, Roberto
AU - Ventura, Natascia
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Aging
KW - Autophagy
KW - Fat
KW - Frataxin
KW - Mitochondria
KW - Nematode
KW - P53/cep-1
UR - http://www.scopus.com/inward/record.url?scp=84872566075&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872566075&partnerID=8YFLogxK
U2 - 10.1016/j.exger.2012.12.002
DO - 10.1016/j.exger.2012.12.002
M3 - Article
C2 - 23247094
AN - SCOPUS:84872566075
VL - 48
SP - 191
EP - 201
JO - Experimental Gerontology
JF - Experimental Gerontology
SN - 0531-5565
IS - 2
ER -