Targeting mitochondrial oxidative phosphorylation: lessons, advantages, and opportunities

Machado, Nicole D.; Heather, Lisa C.; Harris, Adrian L.; Higgins, Geoff S.

doi:10.1038/s41416-023-02394-9

Cited by 11 publications

(2 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding is also supported by a previous report pointing to increased sensitivity of PTEN-deficient fibroblasts to inhibition of mitochondrial complex I in comparison with PTEN-wildtype cells 45 . These observations may be especially significant given the narrow therapeutic index of recently developed complex I inhibitors such as IACS-010759 in clinical trials 46,47 , and highlight the importance of identifying specific subsets of patients that may actually benefit from such therapies despite the side effects. Importantly, loss of PTEN mutations are prevalent and predict poor survival in multiple cancers, including gliomas 39 .…”

Section: Discussionmentioning

confidence: 99%

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Abecunas,

Kidd,

Jiang

et al. 2023

Preprint

View full text Add to dashboard Cite

Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tissue lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings using data from an independent set of cell lines, pharmacological screens, and via single-cell analysis of patient-derived tumors. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating these relationships could inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Abecunas,

Kidd,

Jiang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Usually compounds that disrupt mitochondrial function result in toxic consequences like uncontrolled production of reactive oxygen species, which can induce cell death and lead to serious consequences including drug-induced liver injury and cardiotoxicity in humans (Barbier-Torres et al 2017; Karamanlidis et al 2013). Alternatively, there are several mitochondrial inhibitors such as metformin, nitric oxide, and arsenic trioxide, that are commonly studied in the clinic for potentially beneficial effects (Machado et al 2023). Atovaquone, a specific inhibitor for ETC complex III also showed very promising anti-cancer activity in patients (Xiang et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging

Dutta,

Gerke,

Odron

et al. 2023

Preprint

View full text Add to dashboard Cite

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine spongeC. mycofijiensisand its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), a widely used ETC complex I inhibitor, these two molecules showed cytotoxicity to cancer cells but strikingly demonstrate a lack of toxicity to non-cancer cells, a highly beneficial feature in the development of anti-cancer therapeutics. Furthermore, in vivo experiments with these small molecules utilizingC.elegansmodel demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. Interestingly, we also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilize the transcription factors ATFS-1 and HSF-1, which are involved in the UPRMTand heat shock response (HSR) pathways respectively, 8-OAc only required HSF-1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

show abstract

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging

Dutta,

Gerke,

Odron

et al. 2024

GeroScience

View full text Add to dashboard Cite

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging. Graphical Abstract

show abstract

Targeting mitochondrial oxidative phosphorylation: lessons, advantages, and opportunities

Cited by 11 publications

References 14 publications

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations

Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging

Contact Info

Product

Resources

About