bims-miptne 2024-09-29 papers

Structure. 2024 Sep 17. pii: S0969-2126(24)00363-0. [Epub ahead of print]

An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium.

Qi-Tong Lin, Danielle M Colussi, Taylor Lake, Peter B Stathopulos.

AlphaFold can accurately predict static protein structures but does not account for solvent conditions. Human leucine zipper EF-hand transmembrane protein-1 (LETM1) has one sequence-identifiable EF-hand but how calcium (Ca2+) affects structure and function remains enigmatic. Here, we used highly confident AlphaFold Cα predictions to guide nuclear Overhauser effect (NOE) assignments and structure calculation of the LETM1 EF-hand in the presence of Ca2+. The resultant NMR structure exposes pairing between a partial loop-helix and full helix-loop-helix, forming an unprecedented F-EF-hand with non-canonical Ca2+ coordination but enhanced hydrophobicity for protein interactions compared to calmodulin. The structure also reveals the basis for pH sensing at the link between canonical and partial EF-hands. Functionally, mutations that augmented or weakened Ca2+ binding increased or decreased matrix Ca2+, respectively, establishing F-EF as a two-way mitochondrial Ca2+ regulator. Thus, we show how to synergize AI prediction with NMR data, elucidating a solution-specific and extraordinary LETM1 F-EF-hand.

Keywords: AI/NMR-hybrid structure; AlphaFold; Ca(2+)/H(+) antiporter; F-EF-hand domain; LETM1; calcium sensor; leucine zipper EF-hand containing transmembrane protein-1; oligomerization; pH sensor; solution NMR structure

DOI: https://doi.org/10.1016/j.str.2024.08.020

Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.

Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.

Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

Keywords: LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt

DOI: https://doi.org/10.1016/j.cell.2024.08.045

Pharmacol Res. 2024 Sep 19. pii: S1043-6618(24)00368-2. [Epub ahead of print]209 107423

Human F-ATP synthase as a drug target.

Christoph Gerle, Chimari Jiko, Atsuki Nakano, Ken Yokoyama, Chai C Gopalasingam, Hideki Shigematsu, Kazuhiro Abe.

Practical and conceptual barriers have kept human F-ATP synthase out of reach as a target for the treatment of human diseases. Although this situation has persisted for decades, it may change in the near future. In this review the principal functionalities of human F-ATP synthase--proton motive force / ATP interconversion, membrane bending and mitochondrial permeability transition--are surveyed in the context of their respective potential for pharmaceutical intervention. Further, the technical requirements necessary to allow drug designs that are effective at the multiple levels of functionality and modality of human F-ATP synthase are discussed. The structure-based development of gastric proton pump inhibitors is used to exemplify what might be feasible for human F-ATP synthase. And finally, four structural regions of the human F-ATP synthase are examined as potential sites for the development of structure based drug development.

Keywords: ATP synthase; FoF1 ATPase; OXPHOS; drug design; membrane protein; mitochondria

DOI: https://doi.org/10.1016/j.phrs.2024.107423

Cancer Metastasis Rev. 2024 Sep 23.

The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy.

Fanglu Chen, Yucheng Xue, Wenkan Zhang, Hao Zhou, Zhiyi Zhou, Tao Chen, Eloy YinWang, Hengyuan Li, Zhaoming Ye, Junjie Gao, Shengdong Wang.

Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.

Keywords: Immunotherapy; Metabolism; Mitochondria transfer; Mitochondrial genetics; Mitophagy; Tumor metastasis

DOI: https://doi.org/10.1007/s10555-024-10211-9

bioRxiv. 2024 Sep 09. pii: 2024.09.09.611245. [Epub ahead of print]

Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments.

Mariah J Berner, Heather K Beasley, Zer Vue, Audra Lane, Larry Vang, Mokryun L Baek, Andrea G Marshall, Mason Killion, Faben Zeleke, Bryanna Shao, Dominque Parker, Autumn Peterson, Julie Sterling Rhoades, Estevão Scudese, Lacey E Dobrolecki, Michael T Lewis, Antentor Hinton, Gloria V Echeverria.

Mitochondria are hubs of metabolism and signaling and play an important role in tumorigenesis, therapeutic resistance, and metastasis in many cancer types. Various laboratory models of cancer demonstrate the extraordinary dynamics of mitochondrial structure, but little is known about the role of mitochondrial structure in resistance to anticancer therapy. We previously demonstrated the importance of mitochondrial structure and oxidative phosphorylation in the survival of chemotherapy-refractory triple negative breast cancer (TNBC) cells. As TNBC is a highly aggressive breast cancer subtype with few targeted therapy options, conventional chemotherapies remain the backbone of early TNBC treatment. Unfortunately, approximately 45% of TNBC patients retain substantial residual tumor burden following chemotherapy, associated with abysmal prognoses. Using an orthotopic patient-derived xenograft mouse model of human TNBC, we compared mitochondrial structures between treatment-naïve tumors and residual tumors after conventional chemotherapeutics were administered singly or in combination. We reconstructed 1,750 mitochondria in three dimensions from serial block-face scanning electron micrographs, providing unprecedented insights into the complexity and intra-tumoral heterogeneity of mitochondria in TNBC. Following exposure to carboplatin or docetaxel given individually, residual tumor mitochondria exhibited significant increases in mitochondrial complexity index, area, volume, perimeter, width, and length relative to treatment-naïve tumor mitochondria. In contrast, residual tumors exposed to those chemotherapies given in combination exhibited diminished mitochondrial structure changes. Further, we document extensive intra-tumoral heterogeneity of mitochondrial structure, especially prior to chemotherapeutic exposure. These results highlight the potential for structure-based monitoring of chemotherapeutic responses and reveal potential molecular mechanisms that underlie chemotherapeutic resistance in TNBC.

DOI: https://doi.org/10.1101/2024.09.09.611245