Exploration of Digestive Diseases

Figure 1. Schematic illustration of mitochondrial architecture and function. Mitochondria are conformed by two bilayers separated by the intermembrane space: the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM) [1–3]. The IMM surrounds the mitochondrial matrix, where mitochondrial DNA (mtDNA) and ribosomes are located [4], and it includes the inner boundary membrane (IBM) and mitochondrial cristae. Each bilayer has a specific lipid composition and IMM is specially enriched in proteins [7]. Concretely, mitochondrial cristae contain the respiratory chain complexes and the F1F0-ATP synthase, harboring oxidative phosphorylation to obtain energy. The overflow of electrons between each complex generates reactive oxygen species (ROS) that are reduced by mitochondrial antioxidants, such as glutathione (GSH) [8]. ROS can impair mitochondrial constituents, such as mtDNA, phospholipids, and proteins, leading to cytochrome c (Cyt c) detachment from IMM and releasing it into the cytosol via Bax/Bak oligomerization [4, 5, 9]. Furthermore, ROS production can be enhanced by an altered calcium (Ca²⁺) homeostasis. Mitochondrial dynamics depend on fusion/fission processes. Fusion relies on mitofusin 1/2 (MFN1/2) of the OMM, and optic atrophy protein 1 (OPA1), placed at IMM. In contrast, fission is regulated by dynamin-related protein 1 (Drp-1), which interacts with fission protein 1 (FIS1) [10, 11]. Mitochondria also have a protein machinery to translocate proteins into the matrix. This machinery is composed of the translocase of the outer membrane (TOM) channel the sorting and assembly machinery (SAM) in the OMM and the translocase of the inner membrane (TIM23) in the IBM [12–17]. Ub: ubiquitin; SUMO: small ubiquitin-like modifier; tBID: proapoptotic truncated BID; VDAC: voltage-dependent anion channel; SOD2: superoxide dismutase 2; GPX: glutathione peroxidase; GSSG: glutathione disulfide; O₂^•−: superoxide; OH^–: hydroxyl radical

Note. Adapted from “Electron Transport Chain”, “Mitochondrial Membrane (Phospholipid Bilayers)”, and “Protein Import into the Mitochondria”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates

Declarations

Acknowledgments

Cartoons in Figures were created with BioRender.com. Carmen Garcia-Ruiz and José C. Fernández-Checa acknowledge the support of the Spanish National Research Council’s Cancer Hub.

Author contributions

LF and LCdlR: Conceptualization, Writing—original draft, Writing—review & editing. JCFC and CGR: Conceptualization, Writing—original draft, Writing—review & editing, Funding acquisition, Supervision. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

Prof. José C. Fernández-Checa is the Editor-in-Chief of Exploration of Digestive Diseases, and Prof. Carmen Garcia-Ruiz is a member of the Editorial Board and a Guest Editor of Exploration of Digestive Diseases. However, neither was involved in the decision-making or review process for this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

We are grateful for the support from grants [PID2020-115055RB-I00], [PID2022-1429560B-I00] and [2023AEP068] from Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) and from the CIBEREHD; as well as support from AGAUR of the Generalitat de Catalunya [SGR-2021-00491], European Cooperation in Science & Technology (COST) [ACTION CA17112], Prospective European Drug-Induced Liver Injury Network, the 2018-102799-T “Enfermedades Metabólicas y Cancer” from the Red Nacional of the Spanish Health Ministry and the COVID grant from the Spanish Association for the Study of the Liver (AEEH). In addition, this project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No [101095679]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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