Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
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| Title: | Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. |
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| Authors: | Walker, Emily M., Pearson, Gemma L., Lawlor, Nathan, Stendahl, Ava M., Lietzke, Anne, Sidarala, Vaibhav, Zhu, Jie, Stromer, Tracy, Reck, Emma C., Li, Jin, Levi-D'Ancona, Elena, Pasmooij, Mabelle B., Hubers, Dre L., Renberg, Aaron, Mohamed, Kawthar, Parekh, Vishal S., Zhang, Irina X., Thompson, Benjamin, Zhang, Deqiang, Ware, Sarah A. |
| Source: | Science. 4/11/2025, Vol. 388 Issue 6743, p1-14. 14p. |
| Subjects: | Metabolic disorders, Diabetes, Oxidative phosphorylation, Fat cells, Chromatin |
| Abstract: | Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Pharmacologic blockade of the integrated stress response in vivo restored β cell identity after the loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders. Editor's summary: Metabolic diseases such as type 2 diabetes and metabolic dysfunction–associated steatotic liver disease are increasing in prevalence, and in-depth mechanistic insights and improved therapeutic approaches continue to be needed. Previous studies have identified evidence of mitochondrial dysfunction in these disorders. By examining multiple mouse models and human pancreatic islet beta cells, Walker et al. identified a mechanism whereby abnormalities in mitochondrial quality control pathways can promote dedifferentiation and cellular immaturity in beta cells, hepatocytes, and brown adipocytes, leading to detrimental changes across multiple metabolic tissues. The authors also identified a potential pharmacologic intervention for reversing the observed abnormalities. —Yevgeniya Nusinovich INTRODUCTION: Mitochondrial damage is a hallmark of metabolic diseases, including type 2 diabetes (T2D) and metabolic dysfunction–associated steatotic liver disease (MASLD). Yet, the consequences of impaired mitochondria in metabolic tissues are often unclear. RATIONALE: Defects in mitochondrial structure, gene expression, and energetics previously observed in T2D could arise as a result of impairments in mitochondrial quality control or the mitochondrial life cycle, which tightly regulate mitochondrial genome integrity and replication, biogenesis, fission and fusion dynamics, and turnover by mitophagy. We observed impairments in mitochondrial genome integrity, mitochondrial RNA expression, and mitophagy in pancreatic β cells of donors with T2D. These findings led us to hypothesize that models of impaired mitophagy, mitochondrial genome integrity, or mitochondrial fusion in isolation would allow us to parse the contribution of each mitochondrial quality control defect to β cell failure in T2D. RESULTS: In this study, we report that dysfunctional mitochondrial quality control engaged a retrograde (mitonuclear) signaling program that impaired the function of metabolic tissues owing to dedifferentiation rather than apoptosis. A comparative analysis of the top 500 up- and down-regulated genes by RNA sequencing across our models of mitophagy deficiency, mitochondrial DNA depletion, and defective fusion revealed a common activation of the mitochondrial integrated stress response (mtISR). Single-cell sequencing studies demonstrated that impairments in mitochondrial quality control led to robust changes in chromatin accessibility and gene expression, consistent with engagement of the mtISR, as well as loss of cell identity and maturity that was further confirmed by genetic lineage tracing. We also found that impaired mitochondrial quality control elicited defects in the electron transport chain–oxidative phosphorylation (ETC-OXPHOS) system that ultimately induced the mtISR in both mouse and human β cells. Notably, pharmacologic blockade of mitochondrial retrograde signaling in vivo restored β cell mass and identity to ameliorate hyperglycemia after mitochondrial damage. Moreover, we extended these observations beyond pancreatic β cells to other metabolic tissues, including hepatocytes and brown adipocytes. CONCLUSION: Mitochondrial quality control promotes the identity and maturity of metabolic tissues by restraining retrograde signaling. Targeting mitochondrial retrograde signaling may be promising in the treatment or prevention of diabetes and other metabolic disorders. A retrograde mitochondrial signaling cascade induces the loss of identity and maturity in metabolic tissues.: Numerous defects in the mitochondrial quality control machinery are capable of eliciting defects in the ETC-OXPHOS system, which acts as a retrograde signal to trigger the mtISR. Engagement of the mtISR induces chromatin remodeling and transcriptional and functional immaturity in metabolic tissues. TCA, tricarboxylic acid; ADP, adenosine 5′-diphosphate; ATP, adenosine 5′-triphosphate; BAT, brown adipose tissue. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Pharmacologic blockade of the integrated stress response in vivo restored β cell identity after the loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders. Editor's summary: Metabolic diseases such as type 2 diabetes and metabolic dysfunction–associated steatotic liver disease are increasing in prevalence, and in-depth mechanistic insights and improved therapeutic approaches continue to be needed. Previous studies have identified evidence of mitochondrial dysfunction in these disorders. By examining multiple mouse models and human pancreatic islet beta cells, Walker et al. identified a mechanism whereby abnormalities in mitochondrial quality control pathways can promote dedifferentiation and cellular immaturity in beta cells, hepatocytes, and brown adipocytes, leading to detrimental changes across multiple metabolic tissues. The authors also identified a potential pharmacologic intervention for reversing the observed abnormalities. —Yevgeniya Nusinovich INTRODUCTION: Mitochondrial damage is a hallmark of metabolic diseases, including type 2 diabetes (T2D) and metabolic dysfunction–associated steatotic liver disease (MASLD). Yet, the consequences of impaired mitochondria in metabolic tissues are often unclear. RATIONALE: Defects in mitochondrial structure, gene expression, and energetics previously observed in T2D could arise as a result of impairments in mitochondrial quality control or the mitochondrial life cycle, which tightly regulate mitochondrial genome integrity and replication, biogenesis, fission and fusion dynamics, and turnover by mitophagy. We observed impairments in mitochondrial genome integrity, mitochondrial RNA expression, and mitophagy in pancreatic β cells of donors with T2D. These findings led us to hypothesize that models of impaired mitophagy, mitochondrial genome integrity, or mitochondrial fusion in isolation would allow us to parse the contribution of each mitochondrial quality control defect to β cell failure in T2D. RESULTS: In this study, we report that dysfunctional mitochondrial quality control engaged a retrograde (mitonuclear) signaling program that impaired the function of metabolic tissues owing to dedifferentiation rather than apoptosis. A comparative analysis of the top 500 up- and down-regulated genes by RNA sequencing across our models of mitophagy deficiency, mitochondrial DNA depletion, and defective fusion revealed a common activation of the mitochondrial integrated stress response (mtISR). Single-cell sequencing studies demonstrated that impairments in mitochondrial quality control led to robust changes in chromatin accessibility and gene expression, consistent with engagement of the mtISR, as well as loss of cell identity and maturity that was further confirmed by genetic lineage tracing. We also found that impaired mitochondrial quality control elicited defects in the electron transport chain–oxidative phosphorylation (ETC-OXPHOS) system that ultimately induced the mtISR in both mouse and human β cells. Notably, pharmacologic blockade of mitochondrial retrograde signaling in vivo restored β cell mass and identity to ameliorate hyperglycemia after mitochondrial damage. Moreover, we extended these observations beyond pancreatic β cells to other metabolic tissues, including hepatocytes and brown adipocytes. CONCLUSION: Mitochondrial quality control promotes the identity and maturity of metabolic tissues by restraining retrograde signaling. Targeting mitochondrial retrograde signaling may be promising in the treatment or prevention of diabetes and other metabolic disorders. A retrograde mitochondrial signaling cascade induces the loss of identity and maturity in metabolic tissues.: Numerous defects in the mitochondrial quality control machinery are capable of eliciting defects in the ETC-OXPHOS system, which acts as a retrograde signal to trigger the mtISR. Engagement of the mtISR induces chromatin remodeling and transcriptional and functional immaturity in metabolic tissues. TCA, tricarboxylic acid; ADP, adenosine 5′-diphosphate; ATP, adenosine 5′-triphosphate; BAT, brown adipose tissue. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adf2034 |
