High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo

Bonekamp, Nina A.; Jiang, Min; Motori, Elisa; Villegas, Rodolfo Garcia; Koolmeister, Camilla; Atanassov, Ilian; Mesaros, Andrea; Park, Chan Bae; Larsson, Nils‐Göran

doi:10.26508/lsa.202101034

Cited by 52 publications

(41 citation statements)

References 79 publications

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“…Since the IMT1‐resistant cells maintained higher levels of mtDNA in the presence of IMT1 (Fig 4G ), we investigated whether decreased mtDNA levels could affect survival. To this end, we knocked down the expression of TFAM, which directly controls mtDNA levels (Filograna et al , 2021 ; Bonekamp et al , 2021 ). We used two different small interfering RNAs (siRNAs) in IMT1‐resistant cells and both siRNAs caused a gradual decrease in TFAM protein levels (Fig EV4I ) and mtDNA levels (Fig EV4J ) over time.…”

Section: Resultsmentioning

confidence: 99%

Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

et al. 2021

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Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed smallmolecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.

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Section: Resultsmentioning

confidence: 99%

Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

et al. 2021

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“…Therefore, two known players in the mechanism of complex synthesis of ETC complexes were investigated, namely mitochondrial transcription factor A (TFAM) and heme oxygenase-1 (HO-1). Both have been described as factors that can act both stimulatory [35][36][37] and inhibitory [35,[38][39][40] on mitochondrial biogenesis and ETC complex assembly. In the case of the investigated combination of THC and CBD, a highly variable TFAM upregulation (Figure 6A,B) but a strong and significant induction of HO-1 (Figure 6C,D) was found in both cell lines.…”

Section: Combined Treatment With Thc and Cbd Upregulates The Expressi...mentioning

confidence: 99%

The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

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Theisen

Wendt

et al. 2022

Cancers

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Phytocannabinoids represent a promising approach in glioblastoma therapy. Previous work has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations of psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly increases cell death. In the present work, the glioblastoma cell lines U251MG and U138MG were used to investigate whether the combination of THC and CBD in a 1:1 ratio is associated with a disruption of cellular energy metabolism, and whether this is caused by affecting mitochondrial respiration. Here, the combined administration of THC and CBD (2.5 µM each) led to an inhibition of oxygen consumption rate and energy metabolism. These effects were accompanied by morphological changes to the mitochondria, a release of mitochondrial cytochrome c into the cytosol and a marked reduction in subunits of electron transport chain complexes I (NDUFA9, NDUFB8) and IV (COX2, COX4). Experiments with receptor antagonists and inhibitors showed that the degradation of NDUFA9 occurred independently of the activation of the cannabinoid receptors CB1, CB2 and TRPV1 and of usual degradation processes mediated via autophagy or the proteasomal system. In summary, the results describe a previously unknown mitochondria-targeting mechanism behind the toxic effect of THC and CBD on glioblastoma cells that should be considered in future cancer therapy, especially in combination strategies with other chemotherapeutics.

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“…Mitochondrial DNA is maternally inherited and replicated independently of the host genome but the great majority of the proteins regulating mitochondrial structure, biogenesis and function are encoded by the nuclear genome and imported into the mitochondria. For example, the transcription and replication of mtDNA is regulated by the mitochondrial transcription factor A (TFAM), which is encoded by the nucleus DNA [ 37 ], indicating a clear complex and bidirectional regulation between the nucleus and the mitochondria. Mitochondria has diameter of ~ 0.5 to 1 µm, but their size and structure vary considerably both between different cell types and within the cell [ 38 ].…”

Section: Structure Of Mitochondria: a Unique And Powerhouse Of The Cellmentioning

confidence: 99%

β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?

et al. 2022

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Diabetes mellitus (DM), currently affecting 463 million people worldwide is a chronic disease characterized by impaired glucose metabolism resulting from the loss or dysfunction of pancreatic β-cells with the former preponderating in type 1 diabetes (T1DM) and the latter in type 2 diabetes (T2DM). Because impaired insulin secretion due to dysfunction or loss of pancreatic β-cells underlies different types of diabetes, research has focused its effort towards the generation of pancreatic β-cells from human pluripotent stem cell (hPSC) as a potential source of cells to compensate for insulin deficiency. However, many protocols developed to differentiate hPSCs into insulin-expressing β-cells in vitro have generated hPSC-derived β-cells with either immature phenotype such as impaired glucose-stimulated insulin secretion (GSIS) or a weaker response to GSIS than cadaveric islets. In pancreatic β-cells, mitochondria play a central role in coupling glucose metabolism to insulin exocytosis, thereby ensuring refined control of GSIS. Defects in β-cell mitochondrial metabolism and function impair this metabolic coupling. In the present review, we highlight the role of mitochondria in metabolism secretion coupling in the β-cells and summarize the evidence accumulated for the implication of mitochondria in β-cell dysfunction in DM and consequently, how targeting mitochondria function might be a new and interesting strategy to further perfect the differentiation protocol for generation of mature and functional hPSC-derived β-cells with GSIS profile similar to human cadaveric islets for drug screening or potentially for cell therapy.

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High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo

Cited by 52 publications

References 79 publications

Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?

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