Atlas of Subcellular RNA Localization Revealed by APEX-Seq

https://www.cell.com/cell/fulltext/S0092-8674(19)30555-0

Fazal FM, Han S, Parker KR, Kaewsapsak P, Xu J, Boettiger AN, Chang HY, Ting AY

• The authors introduce the method APEX-seq, which is a method for whole-transcriptome spatial profiling in living cells. It is based on direct proximity labelling of RNA using the peroxidase enzyme APEX2. 
• The APEX protein may be localised to different cellular subcomponents, such as the nucleolus, nuclear pore, endoplasmic reticulum, nuclear lamina, outer mitochondrial membrane, and mitochondrial matrix. Once there, APEX biotinylates mRNAs and proteins, allowing mRNAs from the targeted region to be purified and sequenced through RNA-seq.

Cell population heterogeneity driven by stochastic partition and growth optimality

https://arxiv.org/pdf/1805.07768.pdf

Jorge Fernandez-de-Cossio-Diaz, Roberto Mulet, Alexei Vazquez

• The authors suggest that a cellular quantity which i) has an optimal value for growth rate; ii) is stochastically partitioned at cell division; may display a bimodal distribution in the population. 
• Whether the distribution is unimodal or bimodal depends on the sharpness of (i) and the extent of noise in (ii). The authors suggest mitochondria as a potential cellular component for which their theory is applicable.

Quasi-Mendelian Paternal Inheritance of mitochondrial DNA: A notorious artifact, or anticipated mtDNA behavior?

https://www.biorxiv.org/content/10.1101/660670v1?ct=

Sofia Annis, Zoe Fleischmann, Mark Khrapko, Melissa Franco, Kevin Wasko, Dori Woods, Wolfram S. Kunz, Peter Ellis, Konstantin Khrapko

• A recent publication suggested that biparental inheritance of mtDNA may sometimes occur in humans
• It has since been suggested that these observations may be explained by the presence of mtDNA nuclear pseudogenes (NUMTs) in the father's nuclear genome, rather than biparental inheritance
• The authors of this article suggest another interpretation: that the original authors did in fact observe biparental inheritance of mtDNA, and that the paternal mtDNA was inherited by nascent cells with low copy number, and that the paternal mtDNA had a selective advantage. 
• Using computational modelling (based on this publication), the authors predict a somatic mosaic distribution of paternal mtDNA in the resulting progeny, including in the germline.

Mitochondrial behaviors prime the selective inheritance against harmful mitochondrial DNA mutations

https://www.biorxiv.org/content/biorxiv/early/2019/05/24/646638.full.pdf

Zhe Chen, Zong-Heng Wang, Guofeng Zhang and Hong Xu

• The authors investigate the mechanism of selective inheritance of a deleterious temperature-sensitive mitochondrial DNA mutation in the germline of Drosophila. At 29C, this allele is selected against.
• They show that mitochondria become fragmented such that >90% of organelles contain a single mitochondrial nucleoid in the germarium 2A region of developing Drosophila ovaries. Nucleoids were found to contain 1.3 mtDNAs on average, suggesting that intra-nucleoid complementation is limited.
• Inhibition of fission caused the inter-generational selection against the mutation to essentially be eliminated. 
• They show that in region 2B, mitochondrial transcripts are expressed (shown via fluoresence in-situ hybridization), and the TMRM:MitoTracker ratio is increased by ~x3 fold.
• Knock-down of cox5A resulted in diminished selection, suggesting that activation of mitochondrial respiration is necessary for selection. Similarly, expression of AOX, which by-passes the electron transport chain, resulted in diminished selection. Also, inhibition of mtDNA replication diminished selection (although mean heteroplasmy was also lower in the control setting, at the permissive temperature of 18C, in this case).
• To summarise, the authors demonstrate that mitochondrial fission, combined with a suppression of mtDNA replication, in proliferating germ cells segregates mtDNA into individual organelles. The expression of mtDNA induces a genotype-phenotype correspondence for individual organelles, whereby defective organelles are removed and consequently an elimination of mutated molecules of mtDNA.

Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation

https://elifesciences.org/articles/41351

Cong-Hui Yao, Rencheng Wang, Yahui Wang, Che-Pei Kung, Jason D Weber, Gary J Patti

• The authors show that mouse fibroblasts increase oxidative phosphorylation by nearly x2, and mitochondrial coupling efficiency by ~30%, during proliferation. Both of these changes are supported by mitochondrial fusion.
• Modulating mitochondrial fusion through Mfn2 levels caused modulation in proliferation rate. Decreases in fusion decreased OXPHOS but not ATP levels.
• The authors suggest that cell proliferation requires increased OXPHOS supported by mitochondrial fusion.

Mammalian cell growth dynamics in mitosis

https://elifesciences.org/articles/44700

Teemu P Miettinen, Joon Ho Kang, Lucy F Yang, Scott R Manalis

• The authors use a suspended microchannel resonator and protein synthesis assays to measure the accumulation of cell mass through the cell cycle, for single mammalian cells.
• For various animal cell types, the growth rate in prophase (the first stage of the cell cycle) is comparable to or larger than interphase (the phase where DNA is copied) growth rates. Growth is only stopped in the metaphase-to-anaphase transition. 
• The authors find that a range of mitotic arrest mechanisms inhibit cell growth. Their results counter the traditional idea that cell growth is negligible during mitosis.

Germline selection shapes human mitochondrial DNA diversity

https://science.sciencemag.org/content/364/6442/eaau6520.abstract

Wei Wei, Salih Tuna, Michael J. Keogh, Katherine R. Smith, Timothy J. Aitman, F. Lucy Raymond, Mark Caulfield, Ernest Turro, Patrick F. Chinnery and others

• The authors analyse 1526 mother-offspring pairs from rare-disease patients in the 100,000 genomes project, to show that 45% of individuals display heteroplasmy at >1% variant allele frequency (VAF).
• The authors define 3 kinds of variant: transmitted/inherited (present in both mother and offspring and heteroplasmic in at least one; transmitted = mother, inherited = offspring), lost (present in mother, absent in offspring) and de novo (present in offspring, absent in mother). Absence is defined as VAF < 1%.
• Transmitted variants had a much larger heteroplasmic fraction than lost and de novo variants. 
• Transmitted VAF correlates with inherited VAF (in logit-transformed space).
• Heteroplasmy transmission/inheritance did not display a significantly skewed distribution in the inter-generational VAF shift, which is compatible with this set of mutations undergoing neutral drift.
• The D-loop had an approximately 4 times higher inter-generational mutation rate per base pair than the rest of the mitochondrial genome, suggesting the existence of stronger selective pressures against mutation on the reset of the genome, or potentially an intrinsically lower de novo mutation rate.
• tRNA, rRNA, and non-synonymous mutations tended to have a lower VAF than D-loop and synonymous mutations, suggesting the existence of selection.
• The authors identified haplogroup-matched (92%) and haplogroup-mismatched (2.3%) groups within their dataset (6% could not be identified). Haplogroup mismatching arises from mixed-race ancestry. The heteroplasmic variants in the mismatched group were significantly more likely to match the ancestry of the nuclear genetic background than the mtDNA background on which the heteroplasmy occurred.

Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-likeTumor Cells in Human Prostate Cancer

.https://www.ncbi.nlm.nih.gov/pubmed/31130467

Gianluca Civenni, Roberto Bosotti, Andrea Timpanaro, Ramiro Vàzquez, Jessica Merulla, Shusil Pandit, Simona Rossi, Domenico Albino, Sara Allegrini, Abhishek Mitra, Sarah N. Mapelli, Luca Vierling, Martina Giurdanella, Martina Marchetti, Alyssa Paganoni, Andrea Rinaldi, Marco Losa, Enrica Mira-Catò, Rocco D’Antuono, Diego Morone, Keyvan Rezai, Gioacchino D’Ambrosio, L’Houcine Ouafik, Sarah Mackenzie, Maria E. Riveiro, Esteban Cvitkovic, Giuseppina M. Carbone and Carlo V. Catapano

INTRODUCTION

• Prostate cancer (PC) is the most common neoplasy in men and one of the main causes of cancer death in developed countries.

• Cancer stem cells (CSCs) are a small subset of cancer cells with stem-cell like properties. They contribute to treatment failure and relapse. Understanding the mechanisms which regulate their self-renewal, differentiation and senescence could lead to new therapeutic strategies.

• Mitochondrial reprogramming has important functions in CSCs. Mitochondrial dynamics control  asymmetric cell division, self-renewal, and the fate of stem cells. Fission and clearance of dysfunctional mitochondria avoid senescence and prevent stem cell exhaustion.

MAIN FINDINGS OF THE PAPER

• The authors uncover a novel link between the protein BRD4, mitochondrial dynamics and self-renewal of CSCs.

• Genetic knockdown of BRD4 or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic properties. This is mediated through the  inhibition of  mitochondrial fission factor (Mff) caused by BRD4 knockdown.

• Evidence for this is that suppression of Mff transcription reproduced the effects of BRD4 knockdown, whereas ectopic expression of Mff rescued CSCs from exhaustion. Therefore the authors conclude that targeting mitochondrial plasticity in CSCs is a promising avenue for new and more effective therapies.