Glucose feeds the TCA cycle via circulating lactate

https://www.nature.com/articles/nature24057

Sheng Hui, Jonathan M. Ghergurovich, Raphael J. Morscher, Cholsoon Jang, Xin Teng, Wenyun Lu, Lourdes A. Esparza, Tannishtha Reya, Le Zhan, Jessie Yanxiang Guo, Eileen White & Joshua D. Rabinowitz

• When oxygen is present, it is commonly thought that glucose (derived from the food we eat) is catabolised via glycolysis to pyruvate, which is then transported into mitochondria, fuelling the TCA cycle and oxidative phosphorylation. Alternatively, when oxygen is less available, glucose can be catabolised to lactate.
• Although traditionally thought of as a waste product, it is becoming increasingly clear that lactate can itself be used as a fuel molecule
• Here, the authors investigate the relative contribution of glucose and lactate to feeding the TCA cycle in mice, across various tissues
• In fasting mice, the contribution of glucose to the TCA cycle is primarily via circulating lactate in all tissues except the brain
• The circulatory turnover of lactate is the highest of all metabolites, exceeding that of glucose in both the fed and fasted state
• In tumours, lactate is a primary TCA substrate

Structural Basis of Mitochondrial Transcription Initiation

http://www.sciencedirect.com/science/article/pii/S009286741731262X?via%3Dihub

Hauke S.Hillen, Yaroslav I.Morozov, Azadeh Sarfallah, Dmitry Temiakov, Patrick Cramer

• Transcription of the mitochondrial DNA is a critical aspect of understanding mitochondrial physiology. Not only is this linked to the generation of protein, as per nuclear transcription, there is also a link with the actual replication of mtDNA. Many molecular players are involved in both of these processes. Yet, mitochondrial transcription is not well understood in its details.
• The authors report crystal structures of the protein responsible for mtDNA transcription (mtRNAP) when attached to mtDNA.
• TFAM tethers to mtRNAP to recruit the protein to the mtDNA promoter site.
• TFB2M induces structural changes in mtRNAP to enable it to open mtDNA

Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence

http://www.sciencedirect.com/science/article/pii/S1550413117306113

Song M, Franco A, Fleischer JA, Zhang L, Dorn II GW

• Mitochondrial fragmentation is often considered as harmful. This is often determined by inhibiting fusion fission proteins such as Mfn2 and Opa1. However, such conclusions are confounded by Mfn2 functioning in mitophagy and Opa1 functioning in cristae organisation. The authors sought to determine the role of fusion/fission dynamics in maintaining healthy heart function
• The authors overexpressed the pro-fission protein Drp1 in cardiomyocytes (10 & 25 wild-type expression levels). This induced fragmentation of the network without affecting the expression of other mitochondrial proteins. The fragmented mitochondria appeared healthy
• Through 93 weeks of age, Drp1 overexpression resulted in no phenotype
• Previous work by the authors found that overexpression of Mfn2 induces enlargement of mitochondria in the heart, without any other clear phenotype
• The authors conclude that increased or decreased mitochondrial size alone is not necessarily a mechanism of heart dysfunction
• The authors then investigated a mouse model where Mfn1, Mfn2 and Drp1 expression could be switched off in the adult heart (since knockouts of these proteins are embryonic lethal)
• Abolishing mitochondrial dynamics resulted in: fragmentation of the network, partial depolarisation of mitochondria, parkin aggregation and impaired mitophagy
• Surprisingly, such mice were able to survive 14 weeks after mitochondrial dynamics abrogation (whereas a cardiac knockout of any single one of the 3 genes is rapidly lethal in mice)
• The hearts of such mice were enlarged, and had a mitophagy defect resulting in suppressed elimination of defective mitochondria

Inertial picobalance reveals fast mass fluctuations in mammalian cells

https://www.nature.com/articles/nature24288

David Martínez-Martín, Gotthold Fläschner, Benjamin Gaub, Sascha Martin, Richard Newton, Corina Beerli, Jason Mercer, Christoph Gerber & Daniel J. Müller

• Use a highly sensitive balance to measure the mass of single or multiple adherent cells in culture conditions over days with millisecond time resolution and picogram mass sensitivity 
• The mass of living mammalian cells varies by around 1-4% over timescales of seconds throughout the cell cycle
• These mass fluctuations are linked to ATP synthesis and water transport
• The balance works by oscillating a microcantilever immersed in cell media at the microcantilever's natural frequency. A cell is grown at the tip of the microcantilever. The frequency and amplitude of the vibrations of the microcantilever can be measured using a laser. These data can be used to infer the mass of the cell growing at the tip.
• Blocking aquaporins reduced the amplitude of slow mass fluctuations (period ~17s) by a factor of 4
• Inhibition of ATP synthesis in starved cells reduced the amplitude of slow mass fluctuations by a factor of ~4, and reduced the amplitude of fast mass fluctuations by around 1/3.