Mitochondrial Genome Content Is Regulated during Nematode Development

Tsang, William Y.W.; Lemire, Bernard D.

doi:10.1006/bbrc.2002.6394

Cited by 175 publications

(181 citation statements)

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“…An energy-related developmental checkpoint at the L3 to L4 transition has been proposed in situations of seriously impaired MRC function (41). The C. elegans RNAi phenotypes for prohibitins resemble those of known MRC genes (35) (see also RNAi phenotypes for mev-1 and isp-1 on the World Wide Web at www.wormbase.org/).…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial Prohibitin Complex Is Essential for Embryonic Viability and Germline Function in Caenorhabditis elegans

Artal‐Sanz

Tsang

Willems

et al. 2003

Journal of Biological Chemistry

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189

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Prohibitins in eukaryotes consist of two subunits (PHB1 and PHB2) that together form a high molecular weight complex in the mitochondrial inner membrane. The evolutionary conservation and the ubiquitous expression in mammalian tissues of the prohibitin complex suggest an important function among eukaryotes. The PHB complex has been shown to play a role in the stabilization of newly synthesized subunits of mitochondrial respiratory enzymes in the yeast Saccharomyces cerevisiae. We have used Caenorhabditis elegans as model system to study the role of the PHB complex during development of a multicellular organism. We demonstrate that prohibitins in C. elegans form a high molecular weight complex in the mitochondrial inner membrane similar to that of yeast and humans. By using RNA-mediated gene inactivation, we show that PHB proteins are essential during embryonic development and are required for somatic and germline differentiation in the larval gonad. We further demonstrate that a deficiency in PHB proteins results in altered mitochondrial biogenesis in body wall muscle cells. This paper reports a strong loss of function phenotype for prohibitin gene inactivation in a multicellular organism and shows for the first time that prohibitins serve an essential role in mitochondrial function during organismal development.Prohibitins (Phb1p and Phb2p), referred to here as PHB proteins, are evolutionarily strongly conserved proteins that are located in mitochondria in yeast, plants, and mammals (1-6). In mammalian and yeast cells, it has been demonstrated that PHB proteins associate with each other to form a high molecular weight complex (the PHB complex) in the mitochondrial inner membrane (5, 6). Although diverse cellular functions have been attributed to both PHB proteins (see Ref. 7 for a review), such as a role in cell cycle regulation (8 -11) and in cell surface signaling (12, 13), these functions are difficult to reconcile with the exclusive localization of mammalian PHB proteins to mitochondria (1, 3). To date, studies on the yeast PHB complex have provided convincing evidence for a direct role in mitochondrial function. The PHB complex has been found to co-purify with the m-AAA (matrix-ATPase associated with a variety of cellular activities) protease, and a role as a negative regulator of the protease has been proposed (5). Yeast PHB proteins are capable of stabilizing newly synthesized mitochondrially encoded proteins through direct interaction, suggesting a role in mitochondrial respiratory complex assembly (5, 6). We have suggested a role for PHB proteins in the biogenesis of mitochondria as a holdase/unfoldase type of protein specifically required in situations of metabolic stress (6). Based on structural data from chemical cross-linking and mass spectrometry, we predict a barrel-like structure for the yeast PHB complex, in the cavity of which mitochondrial products might be held (14).At the phenotypic level, disruption of PHB genes in yeast results in a shortening of the replicative life span due to premature...

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Section: Discussionmentioning

confidence: 99%

The Mitochondrial Prohibitin Complex Is Essential for Embryonic Viability and Germline Function in Caenorhabditis elegans

Artal‐Sanz

Tsang

Willems

et al. 2003

Journal of Biological Chemistry

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189

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“…Patp-2::GFP (P for promoter) is widely expressed throughout development in both males and hermaphrodites (our unpublished data). Consistent with the broad spatial and temporal expression, the nuclear-en- coded atp-2 gene is required for embryonic and larval development (Gonczy et al, 2000;Tsang and Lemire, 2002). To determine whether atp-2 and lov-1 are coexpressed, the male-specific neurons of the head and tail were double labeled with Patp-2::GFP and Plov-1::DsRed2 (a 3-kb lov-1 promoter driving expression of Discosoma red fluorescent protein).…”

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confidence: 99%

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

Barr

2005

MBoC

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Caenorhabditis elegans is a powerful model to study the molecular basis of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutations in the polycystic kidney disease (PKD)1 or PKD2 gene, encoding polycystin (PC)-1 or PC-2, respectively. The C. elegans polycystins LOV-1 and PKD-2 are required for male mating behaviors and are localized to sensory cilia. The function of the evolutionarily conserved polycystin/lipoxygenase/␣-toxin (PLAT) domain found in all PC-1 family members remains an enigma. Here, we report that ATP-2, the ␤ subunit of the ATP synthase, physically associates with the LOV-1 PLAT domain and that this interaction is evolutionarily conserved. In addition to the expected mitochondria localization, ATP-2 and other ATP synthase components colocalize with LOV-1 and PKD-2 in cilia. Disrupting the function of the ATP synthase or overexpression of atp-2 results in a male mating behavior defect. We further show that atp-2, lov-1, and pkd-2 act in the same molecular pathway. We propose that the ciliary localized ATP synthase may play a previously unsuspected role in polycystin signaling. INTRODUCTIONAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting one per 400-1000 individuals (Igarashi and Somlo, 2002). This syndrome is characterized by progressive development of fluid-filled, epithelial cysts in the kidney, liver, and pancreas and accounts for ϳ10% of all cases of endstage renal disease. Mutation in either the polycystic kidney disease (PKD)1 or PKD2 gene accounts for 95% of all ADPKD cases. PKD1 encodes polycystin (PC)-1, a 4302-amino acid protein with a large extracellular domain, a G protein-coupled receptor proteolytic site (GPS), 11 predicted transmembrane (TM) domains, and an intracellular C terminus. The polycystin/lipoxygenase/␣-toxin (PLAT) domain is located in the first cytoplasmic loop between TM1 and TM2 and has been postulated to be involved in membrane-protein or protein-protein interactions (Bateman and Sandford, 1999). This domain is conserved in all PC-1 family members and also found in a variety of membrane-or lipid-associated proteins. Polycystin-2 (PC-2, encoded by PKD2) shares homology with the transient receptor protein (TRP) channels and acts as a nonselective cation channel. Defects in PC-1 or PC-2 signaling may result in epithelial dedifferentiation and cyst formation. Several signaling pathways regulated by PC-1 and PC-2 have been identified using in vitro approaches, including G protein signaling, JAK/STAT cell cycle regulation, and mechanotransduction (Boletta and Germino, 2003), but the physiological relevance to normal and disease states remains unclear.The nematode C. elegans is a simple but powerful animal model for studying basic molecular mechanisms underlying human ADPKD. The C. elegans LOV-1 and PKD-2 proteins are homologues of human PC-1 and PC-2 (Barr and Sternberg, 1999;Barr et al., 2001). lov-1 (location of vulva) and pkd-2 act nonredundantly in the same genetic pathway and are requi...

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“…A confounding factor in studies of mtDNA integrity in C. elegans is the presence of large amounts of mtDNA in oocytes, eggs, and juvenile offspring during the reproductive phase of life (Tsang & Lemire, 2002). To avoid this confounder, we used nematodes of a germline proliferation‐deficient ( glp‐1 ) strain for all of our experiments.…”

Section: Resultsmentioning

confidence: 99%

“…To evaluate the physiological relevance (or lack thereof) of these mtDNA deletion burdens in aging C. elegans , it is informative to convert the mutant fraction into units of average number of mutant mtDNA molecules per worm (using 959 cells containing a total of ~300,000 mtDNA molecules per worm (Tsang & Lemire, 2002; Gruber et al, 2011)). Based on our data, a typical worm on average carries 82 ± 9 (mean ± 1 SD over all three age groups) mtDNA molecules with a deletion, irrespective of age.…”

Section: Resultsmentioning

confidence: 99%

“…The copy number of mtDNA per cell is highly dependent on cell type and energy requirements but usually cells contain 1,000–10,000 s of mtDNA (Miller, Rosenfeldt, Zhang, Linnane, & Nagley, 2003). The nematode Caenorhabditis elegans ( C. elegans), a widely used model organism in developmental biology, neurobiology, and aging, comprises 959 cells, together typically containing between 200,000 and 300,000 mtDNA molecules (Gruber et al, 2011; Tsang & Lemire, 2002). The copy number of mtDNA per animal declines with age, with aged nematodes containing almost 30% fewer mtDNA compared to young adults (Gruber et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lakshmanan

Yee

et al. 2018

Aging Cell

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Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (López‐Otín et al., Cell, 153, 2013 and 1194). Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age‐dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age‐dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age‐dependent functional decline commonly observed in C. elegans. Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short‐lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long‐lived animals such as humans and rhesus monkey and possibly in rodents.

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Mitochondrial Genome Content Is Regulated during Nematode Development

Cited by 175 publications

References 27 publications

The Mitochondrial Prohibitin Complex Is Essential for Embryonic Viability and Germline Function in Caenorhabditis elegans

The Mitochondrial Prohibitin Complex Is Essential for Embryonic Viability and Germline Function in Caenorhabditis elegans

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

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