Mitochondrial Impairment by MitoBloCK-6 Inhibits Liver Cancer Cell Proliferation

Kabiri, Yaschar; Fuhrmann, Anna; Becker, Anna; Jedermann, Luisa; Eberhagen, Carola; König, Anika; Silva, Tiago; Borges, Fernanda; Hauck, Stefanie M.; Michalke, Bernhard; Knolle, Percy; Zischka, Hans

doi:10.3389/fcell.2021.725474

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…Analysis of similarities and differences in the structure and function of small TbTims and TbTIM17 complexes with their functional counterparts in other systems is crucial for gaining mechanistic and evolutionary insights into this conserved cellular process in eukaryotes. Notably, it has been shown that redox-regulated small Tims' biogenesis can be targeted by small molecule inhibitors [48,49]. Some human small Tims are involved in functions beyond mitochondrial protein import, such as cytochrome oxidase biogenesis, and mutations in Tim8a are linked with the hereditary disorder, Mohr-Tranebjaerg syndrome [28].…”

Section: Discussionmentioning

confidence: 99%

Unique Interactions of the Small Translocases of the Mitochondrial Inner Membrane (Tims) in Trypanosoma brucei

Quiñones,

Gonzalez,

Darden

et al. 2024

IJMS

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The infectious agent for African trypanosomiasis, Trypanosoma brucei, possesses a unique and essential translocase of the mitochondrial inner membrane, known as the TbTIM17 complex. TbTim17 associates with six small TbTims (TbTim9, TbTim10, TbTim11, TbTim12, TbTim13, and TbTim8/13). However, the interaction patterns of these smaller TbTims with each other and TbTim17 are not clear. Through yeast two-hybrid (Y2H) and co-immunoprecipitation analyses, we demonstrate that all six small TbTims interact with each other. Stronger interactions were found among TbTim8/13, TbTim9, and TbTim10. However, TbTim10 shows weaker associations with TbTim13, which has a stronger connection with TbTim17. Each of the small TbTims also interacts strongly with the C-terminal region of TbTim17. RNAi studies indicated that among all small TbTims, TbTim13 is most crucial for maintaining the steady-state levels of the TbTIM17 complex. Further analysis of the small TbTim complexes by size exclusion chromatography revealed that each small TbTim, except for TbTim13, is present in ~70 kDa complexes, possibly existing in heterohexameric forms. In contrast, TbTim13 is primarily present in the larger complex (>800 kDa) and co-fractionates with TbTim17. Altogether, our results demonstrate that, relative to other eukaryotes, the architecture and function of the small TbTim complexes are specific to T. brucei.

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Section: Discussionmentioning

confidence: 99%

Unique Interactions of the Small Translocases of the Mitochondrial Inner Membrane (Tims) in Trypanosoma brucei

Quiñones,

Gonzalez,

Darden

et al. 2024

IJMS

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show abstract

“…This suggests that ALR is a significant factor in the process of liver regeneration ( Fausto, 1991 ; Gandhi et al, 1999 ; Polimeno et al, 2011 ). The use of MitoBloCK-6 to pharmacologically inhibit ALR reduced the proliferation of hepatocellular carcinoma cells, an effect that links ALR function to mitochondrial iron homeostasis ( Kabiri et al, 2021 ). Silencing of ALR inhibited the proliferation and triggered the apoptosis of U266 human multiple myeloma cells ( Zeng et al, 2017 ).…”

Section: Genetic Factors In Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) occurs in 25% of the global population and manifests as lipid deposition, hepatocyte injury, activation of Kupffer and stellate cells, and steatohepatitis. Predominantly expressed in hepatocytes, the augmenter of liver regeneration (ALR) is a key factor in liver regulation that can alleviate fatty liver disease and protect the liver from abnormal liver lipid metabolism. ALR has three isoforms (15-, 21-, and 23-kDa), amongst which 23-kDa ALR is the most extensively studied. The 23-kDa ALR isoform is a sulfhydryl oxidase that resides primarily in the mitochondrial intermembrane space (IMS), whereby it protects the liver against various types of injury. In this review, we describe the role of ALR in regulating hepatocytes in the context of NAFLD. We also discuss questions about ALR that remain to be explored in the future. In conclusion, ALR appears to be a promising therapeutic target for treating NAFLD.

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“…On the other hand, MB-6 inhibits the sulfhydryl oxidase Erv1 and, in turn, Mia40 function in the import of intermembrane space proteins ( 180 , 181 ). Interestingly, the human homolog of Erv1 (ALR) is found upregulated in hepatocellular carcinoma cell lines and tissues, while its silencing or inhibition through MB-6 impairs mitochondrial function and inhibits the proliferation of liver cancer cells ( 157 , 182 ). MitoBloCKs can be a useful tool to study the role of mitochondrial translocation machinery in cancer, and the transcriptional and proteomic responses induced by accumulation of precursors in the cytosol, following the inhibition of protein import.…”

Section: Mitochondrial Translation-targeted Therapy In Human Cancersmentioning

confidence: 99%

Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

et al. 2021

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Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches.

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Mitochondrial Impairment by MitoBloCK-6 Inhibits Liver Cancer Cell Proliferation

Cited by 4 publications

References 46 publications

Unique Interactions of the Small Translocases of the Mitochondrial Inner Membrane (Tims) in Trypanosoma brucei

Unique Interactions of the Small Translocases of the Mitochondrial Inner Membrane (Tims) in Trypanosoma brucei

The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

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