An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress

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Vergani-Junior, Carlos A. ; Moro, Raissa De P. ; Pinto, Silas ; De-Souza, Evandro A. ; Camara, Henrique ; Braga, Deisi L. ; Tonon-da-Silva, Guilherme ; Knittel, Thiago L. ; Ruiz, Gabriel P. ; Ludwig, Raissa G. ; Massirer, Katlin B. ; Mair, William B. ; Mori, Marcelo A.

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 15, n. 1, p. 15-pg., 2024-04-09.

Abstract

Cellular response to redox imbalance is crucial for organismal health. microRNAs are implicated in stress responses. ALG-1, the C. elegans ortholog of human AGO2, plays an essential role in microRNA processing and function. Here we investigated the mechanisms governing ALG-1 expression in C. elegans and the players controlling lifespan and stress resistance downstream of ALG-1. We show that upregulation of ALG-1 is a shared feature in conditions linked to increased longevity (e.g., germline-deficient glp-1 mutants). ALG-1 knockdown reduces lifespan and oxidative stress resistance, while overexpression enhances survival against pro-oxidant agents but not heat or reductive stress. R02D3.7 represses alg-1 expression, impacting oxidative stress resistance at least in part via ALG-1. microRNAs upregulated in glp-1 mutants (miR-87-3p, miR-230-3p, and miR-235-3p) can target genes in the protein disulfide isomerase pathway and protect against oxidative stress. This study unveils a tightly regulated network involving transcription factors and microRNAs which controls organisms' ability to withstand oxidative stress. In this study, Vergani-Junior et al. show that increased expression of the argonaute ALG-1 in long-lived worms improves oxidative stress resistance through the modulation of microRNAs that downregulate the protein disulfide isomerase pathway. (AU)

• FAPESP's process: 17/01339-2 - Uncovering mechanisms of longevity mediated by mobile RNAs
• Grantee: Henrique Camara
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/25958-9 - DecAI: decoding aging initiative
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/01184-9 - CAMeLEOm: cross-species analysis of metabolic, lifespan effects and omics of dietary restriction mimetics
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
• Grantee: Katlin Brauer Massirer
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/04726-2 - Investigation of new tissue-specific mechanisms of aging control by caloric restriction in C. elegans
• Grantee: Thiago Leite Knittel
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/05851-8 - Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system
• Grantee: Evandro Araújo de Souza
• Support Opportunities: Generation Project Research Grant
• FAPESP's process: 17/23920-9 - Varredura e caracterização de moléculas circulantes que afetam o gasto energético
• Grantee: Raissa Guimarães Ludwig
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/01587-1 - Study of the role of ALG-1 and its regulatory mechanisms in healthspan of Caenorhabditis elegans
• Grantee: Carlos Alberto Vergani Junior
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 23/08316-9 - Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system
• Grantee: Evandro Araújo de Souza
• Support Opportunities: Scholarships in Brazil - Generation Project
• FAPESP's process: 14/10814-8 - Determination of factors that controls Dicer expression in vivo in C. elegans
• Grantee: Evandro Araújo de Souza
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/11792-9 - Characterization in C. elegans of novel genes involved in aging and the evolutionarily conserved mechanisms of dietary restriction mimetics
• Grantee: Deisi Lilian Braga Shimo
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• FAPESP's process: 18/21635-8 - Study of the role of miR-203-3p in adipose tissue metabolism and in the pathogenesis of metabolic diseases in mice
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• FAPESP's process: 16/15958-3 - Soma-germline interaction and its effect on longevity: the role of argonautes in aging C. elegans
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• FAPESP's process: 17/04377-2 - Study of Dicer effects on mitochondrial function, metabolism and aging in C. elegans nematodes
• Grantee: Silas Pinto da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate