Tuesday, 23 April 2019

Intramitochondrial transfer and engineering of mammalian mitochondrial genomes in yeast

https://www.sciencedirect.com/science/article/pii/S1567724918300370?via%3Dihub

Yoon YG, Koob MD


  • The authors demonstrate that entire mouse mtDNA can be stably transferred to the mitochondrial network in yeast which have been depleted of their own native mtDNA.
  • The yeast cells which contained the full mouse mtDNA genome, replicated the mouse mtDNA molecules without detectable sequence alterations or rearrangements.

Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy

https://www.nature.com/articles/s41467-019-09566-3

Zhang W, Hu X, Shen Q, Xing D
  • Many cancer cells over-produce reactive oxygen species by ~10-fold relative to normal cells, providing a biomarker for cancer cells.
  • The authors sought to design a chemical system which targets ROS-overproducing cells, and then further stimulate long-term ROS overproduction inside mitochondria, to induce apoptosis.

Mitochondrial Protein Synthesis and mtDNA Levels Coordinated through an Aminoacyl-tRNA Synthetase Subunit

https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30329-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124719303298%3Fshowall%3Dtrue

Picchioni D, Antolin-Fontes A, Camacho N, Schmitz C, Pons-Pons A, Rodríguez-Escribà M, Machallekidou A, Güler MN, Siatra P, Carretero-Junquera M, Serrano A, Hovde SL, Knobel PA, Novoa EM, Solà-Vilarrubias M, Kaguni LS, Stracker TH, Ribas de Pouplana L


  • The authors investigate a signalling pathway which couples mtDNA translation to mtDNA copy number 
  • They identify a protein (SLIMP) which is essential for mitochondrial respiration, and is involved in tRNA-serine aminoacylation
  • SLIMP interacts with the protein LON, which degrades TFAM. TFAM is a protein involved in forming mtDNA-protein complexes known as nucleoids. Reduction in TFAM levels is associated with mtDNA depletion.
  • Hence mitochondrial translation is directly coupled to mtDNA copy number.

Thursday, 18 April 2019

Mitochondrial volume fraction controls translation of nuclear-encoded mitochondrial proteins

https://www.biorxiv.org/content/biorxiv/early/2019/01/25/529289.full.pdf

Tatsuhisa Tsuboi, Matheus P. Viana, Fan Xu, Jingwen Yu, Raghav Chanchani, Ximena G. Arceo, Evelina Tutucci, Joonhyuk Choi, Yang S. Chen, Robert H. Singer, Susanne M. Rafelski, Brian M. Zid

  • The authors investigate the physiological impact of nuclear-encoded mitochondrial mRNA localization to mitochondria in yeast
  • They observe that as yeast switches to oxidative metabolism, the cytoplasmic density of mitochondria increases (i.e. the ratio of mitochondrial volume to cytoplamic volume)
  • Increases in mitochondrial density drives the localisation of nuclear-encoded mitochondrial mRNAs to the mitochondrial surface, increasing mitochondrial protein production
  • Sequestering mRNAs away from the mitochondrial surface is sufficient to reduce mitochondrial protein production
  • This suggests that mitochondrial density is a physiologically important parameter, which is sensed to regulate mitochondrial gene expression via mRNA localisation.

Wednesday, 17 April 2019

A non‐death function of the mitochondrial apoptosis apparatus in immunity

http://emboj.embopress.org/content/early/2019/04/12/embj.2018100907

Dominik Brokatzky, Benedikt Dörflinger, Aladin Haimovici, Arnim Weber, Susanne Kirschnek, Juliane Vier, Arlena Metz, Julia Henschel, Tobias Steinfeldt, Ian E. Gentle and Georg Häcke

INTRODUCTION
Apoptosis mostly proceeds through mitochondria: the outer mitochondrial membrane is permeabilized, in a process called mitochondrial outer membrane permeabilization (MOMP). This releases cytochrome c to activate cytosolic caspases, which execute apoptosis through proteolysis of numerous substrates.

Recently, it has been observed that apoptosis signaling may be initiated at a low level, in the absence of cell death. Only few mitochondria are permeabilized, and small amounts of cytochrome c are released, causing only limited caspase activation. Apoptosis appears to be triggered but then aborted before the point of no return. The process has been termed minority MOMP and the cell stays alive and can presumably repair any damage caused


MAIN FACTS OF THE PAPER
The author hypothesise that low-level (sub-lethal) “apoptosis” signaling (minority MOMP) can trigger cytokine secretion, causing inflammation and immune alert. Full apoptosis activates caspases that counteract this immune function. The small amounts of caspase activated during sub-lethal signaling following minority MOMP may however be too low to turn the signal off, resulting in cytokine secretion and immune activation.

Infecting HeLa cells by several agents, they tested this possibility and reported that human cells can react to low-level apoptosis induction with cytokine secretion. Minority MOMP was detected with all infectious agents tested. This suggests that minority MOMP is a very common occurrence during infection. In addition, the authors show that the ability of epithelial cells to fight the growth of parasites is decreased when proapoptotic signaling is deleted.


CONCLUSIONS
Their results suggest that mitochondria have a function in the detection of microbial infection and cell-autonomous immunity, through a sub-lethal (low-intensity) activation of the mitochondrial apoptosis apparatus.

They also report damage to the genomic DNA caused by the mitochondrial apoptosis signaling. Since MOMP seems like a frequent occurrence, this suggests that infection-associated damage to the genomic DNA is widespread. Therefore, this study also identifies DNA damage as a common occurrence during infection and indicate the possibility that infection-associated mutations, potentially leading to cancer, may be a side effect of this system of microbial detection.

Monday, 15 April 2019

Mitochondrial origins of fractional control in regulated cell death

https://www.nature.com/articles/s41467-019-09275-x.pdf

Luís C. Santos, Robert Vogel, Jerry E. Chipuk, Marc R. Birtwistle, Gustavo Stolovitzky & Pablo Meyer


  • The authors investigate cell-to-cell variability in cell death in response to TNF-related apoptosis inducing ligand (TRAIL), an apoptosis-inducing drug.
  • The authors find that with successively increasing doses of TRAIL, the probability distribution of mitochondrial density (which the authors define as MitoTracker Deep Red fluoresence intensity divided by forward scatter) becomes increasingly enriched for cells with high mitochondrial density -- suggesting that high cytoplasmic mitochondrial density is required for TRAIL resistance (in contrast to this)
  • The authors point out that the steepness of a dose-response curve is a measure of cell-to-cell variability in cellular sensitivity to a stimulus, and derive a formalism to convert a Hill function into a probability distribution over cellular stimulus thresholds for a binary response variable (such as cell death). They derive an approximate expansion of the sensitivity threshold in terms of the half maximal inhibitory concentration (IC50), and the log ratio of mitochondrial density to mean mitochondrial density. This results in an expression for the conditional probability of a cell being alive given a biological quantity of interest, e.g. mitochondrial density (see Eq 4)
  • The authors attribute this correlation to variable effective concentrations of pro-apoptotic proteins on the mitochondrial outer membrane
  • The authors suggest that anti-apoptotic Bcl-2 family proteins may increase the variance in cell death response, potentially enhancing resistance to treatment