Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
{"title":"Mechanisms and disease relevance of mitochondrial translation in humans.","authors":"Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach","doi":"10.1038/s41580-026-00948-2","DOIUrl":"https://doi.org/10.1038/s41580-026-00948-2","url":null,"abstract":"<p><p>Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.</p>","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":90.2,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1038/s41580-026-00950-8
Lisa Heinke
Liquid–liquid phase separation of the endoplasmic reticulum (ER)-resident protein PDZD8 leads to the formation of biomolecular condensates that stabilize ER–mitochondria contact sites.
{"title":"Organelles stick together through PDZD8-mediated condensate formation","authors":"Lisa Heinke","doi":"10.1038/s41580-026-00950-8","DOIUrl":"10.1038/s41580-026-00950-8","url":null,"abstract":"Liquid–liquid phase separation of the endoplasmic reticulum (ER)-resident protein PDZD8 leads to the formation of biomolecular condensates that stabilize ER–mitochondria contact sites.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 3","pages":"175-175"},"PeriodicalIF":90.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1038/s41580-025-00945-x
W Mike Henne,Sarah Cohen
Lipid droplets (LDs) are emerging as key factors in cellular physiology, with roles beyond energy storage, including metabolic homeostasis, signalling and development. Together with a growing list of functions, diverse LD populations are being identified in different tissue types as well as within the context of single cells. Here we summarize recent work highlighting LD diversity from three perspectives: their lipid and protein compositional heterogeneity; differences in abundance, size and spatial organization within cells; and the diverse contacts they form with other organelles, all of which contribute to LD function. We also discuss tools and approaches used to visualize LD heterogeneity, the role of LDs in pathophysiology and disease, and open questions in the field.
{"title":"Heterogeneity, dynamics and organelle interactions of lipid droplets.","authors":"W Mike Henne,Sarah Cohen","doi":"10.1038/s41580-025-00945-x","DOIUrl":"https://doi.org/10.1038/s41580-025-00945-x","url":null,"abstract":"Lipid droplets (LDs) are emerging as key factors in cellular physiology, with roles beyond energy storage, including metabolic homeostasis, signalling and development. Together with a growing list of functions, diverse LD populations are being identified in different tissue types as well as within the context of single cells. Here we summarize recent work highlighting LD diversity from three perspectives: their lipid and protein compositional heterogeneity; differences in abundance, size and spatial organization within cells; and the diverse contacts they form with other organelles, all of which contribute to LD function. We also discuss tools and approaches used to visualize LD heterogeneity, the role of LDs in pathophysiology and disease, and open questions in the field.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"15 4 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1038/s41580-025-00944-y
Masaaki Komatsu,Nobuo N Noda,Toshifumi Inada
UFMylation is a ubiquitin-like post-translational modification that has a central role in ribosome-associated quality control at the endoplasmic reticulum (ER-RQC). Through a dedicated enzymatic cascade, UFM1 is conjugated to select substrates, notably the 60S ribosomal subunit protein RPL26, to maintain endoplasmic reticulum and ribosomal integrity under cellular stress. This Review focuses on the structural and mechanistic basis of UFMylation in ER-RQC and its contribution to proteostasis. Although recent studies have identified a growing number of putative UFM1-modified proteins across diverse cellular pathways, the physiological importance of many of these substrates remains unclear. We highlight both the emerging functional breadth of UFMylation and the need for caution in interpreting substrate relevance. UFMylation is increasingly linked to disease, including neurodevelopmental disorders and cancer, underscoring its biological importance. Together, these findings position UFMylation as a key regulatory system connecting endoplasmic reticulum function to broader stress responses.
{"title":"The mechanistic basis and cellular functions of UFMylation.","authors":"Masaaki Komatsu,Nobuo N Noda,Toshifumi Inada","doi":"10.1038/s41580-025-00944-y","DOIUrl":"https://doi.org/10.1038/s41580-025-00944-y","url":null,"abstract":"UFMylation is a ubiquitin-like post-translational modification that has a central role in ribosome-associated quality control at the endoplasmic reticulum (ER-RQC). Through a dedicated enzymatic cascade, UFM1 is conjugated to select substrates, notably the 60S ribosomal subunit protein RPL26, to maintain endoplasmic reticulum and ribosomal integrity under cellular stress. This Review focuses on the structural and mechanistic basis of UFMylation in ER-RQC and its contribution to proteostasis. Although recent studies have identified a growing number of putative UFM1-modified proteins across diverse cellular pathways, the physiological importance of many of these substrates remains unclear. We highlight both the emerging functional breadth of UFMylation and the need for caution in interpreting substrate relevance. UFMylation is increasingly linked to disease, including neurodevelopmental disorders and cancer, underscoring its biological importance. Together, these findings position UFMylation as a key regulatory system connecting endoplasmic reticulum function to broader stress responses.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"21 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41580-025-00940-2
Gangshun Yi, Dimitrios Mamalis
In this Tools of the Trade article, Yi and Mamalis (Gilbert and Davis labs) discuss the development of Di-Gembodies, innovative constructs designed to overcome key challenges in applying cryo-electron microscopy to small proteins that are otherwise difficult to resolve.
{"title":"Engineered nanobodies facilitate cryo-EM studies of small proteins","authors":"Gangshun Yi, Dimitrios Mamalis","doi":"10.1038/s41580-025-00940-2","DOIUrl":"10.1038/s41580-025-00940-2","url":null,"abstract":"In this Tools of the Trade article, Yi and Mamalis (Gilbert and Davis labs) discuss the development of Di-Gembodies, innovative constructs designed to overcome key challenges in applying cryo-electron microscopy to small proteins that are otherwise difficult to resolve.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 3","pages":"174-174"},"PeriodicalIF":90.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1038/s41580-025-00936-y
George Hajishengallis, Triantafyllos Chavakis
{"title":"Inflammageing and clonal haematopoiesis interplay and their impact on human disease","authors":"George Hajishengallis, Triantafyllos Chavakis","doi":"10.1038/s41580-025-00936-y","DOIUrl":"https://doi.org/10.1038/s41580-025-00936-y","url":null,"abstract":"","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"259 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s41580-025-00942-0
Hao Wu, Hongmei Wang
Human stem cell-based embryo models (hSCBEMs) are emerging as powerful tools in biomedical research owing to their ability to recapitulate the cellular, molecular and structural features of human embryos. These models offer new opportunities to advance our understanding of embryogenesis and to find applications in assisted reproduction, regenerative medicine, precision medicine and drug development. Despite rapid progress, challenges remain in improving the structural, cellular and molecular fidelity, efficiency and standardization of hSCBEMs. This Review discusses recent advances in the development of hSCBEMs and key challenges in their construction and applications, and highlights their translational potential while emphasizing the importance of ethical frameworks and public engagement. This Review discusses recent advances and key challenges in the development of human stem cell-based embryo models, and highlights their applications in fundamental biology and translational potential while emphasizing the importance of ethical frameworks and public engagement.
{"title":"Progress in stem cell-based embryo models and their applications in developmental biology and biomedicine","authors":"Hao Wu, Hongmei Wang","doi":"10.1038/s41580-025-00942-0","DOIUrl":"10.1038/s41580-025-00942-0","url":null,"abstract":"Human stem cell-based embryo models (hSCBEMs) are emerging as powerful tools in biomedical research owing to their ability to recapitulate the cellular, molecular and structural features of human embryos. These models offer new opportunities to advance our understanding of embryogenesis and to find applications in assisted reproduction, regenerative medicine, precision medicine and drug development. Despite rapid progress, challenges remain in improving the structural, cellular and molecular fidelity, efficiency and standardization of hSCBEMs. This Review discusses recent advances in the development of hSCBEMs and key challenges in their construction and applications, and highlights their translational potential while emphasizing the importance of ethical frameworks and public engagement. This Review discusses recent advances and key challenges in the development of human stem cell-based embryo models, and highlights their applications in fundamental biology and translational potential while emphasizing the importance of ethical frameworks and public engagement.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 3","pages":"178-193"},"PeriodicalIF":90.2,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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