RESUMEN
Precise regulation of mitochondrial fusion and fission is essential for cellular activity and animal development. Imbalances between these processes can lead to fragmentation and loss of normal membrane potential in individual mitochondria. In this study, we show that MIRO-1 is stochastically elevated in individual fragmented mitochondria and is required for maintaining mitochondrial membrane potential. We further observe a higher level of membrane potential in fragmented mitochondria in fzo-1 mutants and wounded animals. Moreover, MIRO-1 interacts with VDAC-1, a crucial mitochondrial ion channel located in the outer mitochondrial membrane, and this interaction depends on the residues E473 of MIRO-1 and K163 of VDAC-1. The E473G point mutation disrupts their interaction, resulting in a reduction of the mitochondrial membrane potential. Our findings suggest that MIRO-1 regulates membrane potential and maintains mitochondrial activity and animal health by interacting with VDAC-1. This study provides insight into the mechanisms underlying the stochastic maintenance of membrane potential in fragmented mitochondria.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/genética , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Canal Aniónico 1 Dependiente del Voltaje/genética , Canal Aniónico 1 Dependiente del Voltaje/metabolismoRESUMEN
Organisms respond to tissue damage through the upregulation of protective responses which restore tissue structure and metabolic function. Mitochondria are key sources of intracellular oxidative metabolic signals that maintain cellular homeostasis. Here we report that tissue and cellular wounding triggers rapid and reversible mitochondrial fragmentation. Elevated mitochondrial fragmentation either in fzo-1 fusion-defective mutants or after acute drug treatment accelerates actin-based wound closure. Wounding triggered mitochondrial fragmentation is independent of the GTPase DRP-1 but acts via the mitochondrial Rho GTPase MIRO-1 and cytosolic Ca2+. The fragmented mitochondria and accelerated wound closure of fzo-1 mutants are dependent on MIRO-1 function. Genetic and transcriptomic analyzes show that enhanced mitochondrial fragmentation accelerates wound closure via the upregulation of mtROS and Cytochrome P450. Our results reveal how mitochondrial dynamics respond to cellular and tissue injury and promote tissue repair.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Proteínas Mitocondriales/metabolismo , Cicatrización de Heridas/fisiología , Proteínas de Unión al GTP rho/metabolismo , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Calcio/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , GTP Fosfohidrolasas/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Oxidación-Reducción , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Unión al GTP rho/genéticaRESUMEN
Mitochondria are the central hub for many metabolic processes, including the citric acid cycle, oxidative phosphorylation, and fatty acid oxidation. Recent studies have identified a new mitochondrial protein family, Fam210, that regulates bone metabolism and red cell development in vertebrates. The model organism Caenorhabditis elegans has a Fam210 gene, y56a3a.22, but it lacks both bones and red blood cells. In this study, we report that Y56A3A.22 plays a crucial role in regulating mitochondrial protein homeostasis and reproduction. The nematode y56a3a.22 is expressed in various tissues, including the intestine, muscle, hypodermis, and germline, and its encoded protein is predominantly localized in mitochondria. y56a3a.22 deletion mutants are sterile owing to impaired oogenesis. Loss of Y56A3A.22 induced mitochondrial unfolded protein response (UPRmt), which is mediated through the ATFS-1-dependent pathway, in tissues such as the intestine, germline, hypodermis, and vulval muscle. We further show that infertility and UPRmt induces by Y56A3A.22 deficiency are not attributed to systemic iron deficiency. Together, our study reveals an important role of Y56A3A.22 in regulating mitochondrial protein homeostasis and oogenesis and provides a new genetic tool for exploring the mechanisms regulating mitochondrial metabolism and reproduction as well as the fundamental role of the Fam210 family.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Mitocondrias/genética , Oogénesis/genética , Factores de Transcripción/genética , Respuesta de Proteína Desplegada/genética , Animales , Huesos/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Eritrocitos/metabolismo , Femenino , Células Germinativas/crecimiento & desarrollo , Células Germinativas/metabolismo , Humanos , Intestinos/crecimiento & desarrollo , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Reproducción/genética , Transducción de Señal/genética , Vulva/crecimiento & desarrollo , Vulva/metabolismoRESUMEN
The development of genome editing techniques based on CRISPR (Clustered regularly interspaced short palindromic repeats)-Cas9 system has revolutionized biomedical researches. It can be utilized to edit genome sequence in almost any organisms including Caenorhabditis elegans, one of the most convenient and classic genetic model animals. The application of CRISPR-Cas9 mediated genome editing in C. elegans promotes the functional analysis of gene and proteins under many physiological conditions. In this mini-review, we summarized the development of CRISPR-Cas9-based genome editing in C. elegans.
