bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2024‒03‒10
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.
  2. NDUFS4 regulates cristae remodeling in diabetic kidney disease.
  1. Cell Rep. 2024 Mar 06. pii: S2211-1247(24)00191-8. [Epub ahead of print]43(3): 113863
    Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.
    Lydia Grmai, Manuel Michaca, Emily Lackner, Narayanan Nampoothiri V P, Deepika Vasudevan.
      Reproduction is an energy-intensive process requiring systemic coordination. However, the inter-organ signaling mechanisms that relay nutrient status to modulate reproductive output are poorly understood. Here, we use Drosophila melanogaster as a model to establish the integrated stress response (ISR) transcription factor, Atf4, as a fat tissue metabolic sensor that instructs oogenesis. We demonstrate that Atf4 regulates lipase activity to mediate yolk lipoprotein synthesis in the fat body. Depletion of Atf4 in the fat body also blunts oogenesis recovery after amino acid deprivation and re-feeding, suggestive of a nutrient-sensing role for Atf4. We also discovered that Atf4 promotes secretion of a fat-body-derived neuropeptide, CNMamide, which modulates neural circuits that promote egg-laying behavior (ovulation). Thus, we posit that ISR signaling in fat tissue acts as a "metabolic sensor" that instructs female reproduction-directly by impacting yolk lipoprotein production and follicle maturation and systemically by regulating ovulation.
    Keywords:  Atf4; CNMa; CP: Cell biology; CP: Developmental biology; adipocyte; bmm; egg retention; integrated stress response; oogenesis; ovulation; yolk protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.113863
  2. Nat Commun. 2024 Mar 04. 15(1): 1965
    NDUFS4 regulates cristae remodeling in diabetic kidney disease.
    Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.
      The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
    DOI:  https://doi.org/10.1038/s41467-024-46366-w
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