Research on mitochondria and mitochondrial fission

Moved from this thread:
Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in ME/CFS - 2020 - Schreiner
_______________________

https://www.ncbi.nlm.nih.gov/pubmed/26816379

Science. 2016 Jan 15;351(6270):275-281. doi: 10.1126/science.aab4138.
Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress.
Toyama EQ#1, Herzig S#1, Courchet J2, Lewis TL Jr2, Losón OC3, Hellberg K1, Young NP1, Chen H3, Polleux F2, Chan DC3, Shaw RJ1.
Author information
Abstract
Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.

Copyright © 2016, American Association for the Advancement of Science.

Comment in

• Cell biology: Form follows function for mitochondria. [Nature. 2016]
• AMPK Promotes Autophagy by Facilitating Mitochondrial Fission. [Cell Metab. 2016]

PMID:
26816379
PMCID:
PMC4852862
DOI:
10.1126/science.aab4138
[Indexed for MEDLINE]
Free PMC Article

 

https://www.ncbi.nlm.nih.gov/pubmed/28919076

Cell. 2017 Oct 5;171(2):385-397.e11. doi: 10.1016/j.cell.2017.08.018. Epub 2017 Sep 14.
Mitochondrial Priming by CD28.
Klein Geltink RI1, O'Sullivan D1, Corrado M1, Bremser A2, Buck MD1, Buescher JM1, Firat E3, Zhu X4, Niedermann G5, Caputa G1, Kelly B1, Warthorst U6, Rensing-Ehl A6, Kyle RL1, Vandersarren L7, Curtis JD1, Patterson AE1, Lawless S1, Grzes K1, Qiu J1, Sanin DE1, Kretz O8, Huber TB9, Janssens S7, Lambrecht BN7, Rambold AS2, Pearce EJ10, Pearce EL11.
Author information
Abstract
T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.

Copyright © 2017 Elsevier Inc. All rights reserved.

KEYWORDS:
CD28; CD8 T cells; Cpt1a; adoptive cellular immunotherapy; costimulation; memory T cells; mir33; mitochondrial cristae remodeling; mitochondrial morphology; spare respiratory capacity

PMID:
28919076
PMCID:
PMC5637396
DOI:
10.1016/j.cell.2017.08.018
[Indexed for MEDLINE]
Free PMC Article

 

https://www.ncbi.nlm.nih.gov/pubmed/24482226

J Biol Chem. 2014 Mar 21;289(12):8106-20. doi: 10.1074/jbc.M113.511535. Epub 2014 Jan 30.
Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle.
DeBalsi KL1, Wong KE, Koves TR, Slentz DH, Seiler SE, Wittmann AH, Ilkayeva OR, Stevens RD, Perry CG, Lark DS, Hui ST, Szweda L, Neufer PD, Muoio DM.
Author information
Abstract
Thioredoxin-interacting protein (TXNIP) is an α-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herein, we employed targeted metabolomics and comprehensive bioenergetic analyses to evaluate oxidative metabolism and respiratory kinetics in mouse models of total body (TKO) and skeletal muscle-specific (TXNIP(SKM-/-)) Txnip deficiency. Compared with littermate controls, both TKO and TXNIP(SKM-/-) mice had reduced exercise tolerance in association with muscle-specific impairments in substrate oxidation. Oxidative insufficiencies in TXNIP null muscles were not due to perturbations in mitochondrial mass, the electron transport chain, or emission of reactive oxygen species. Instead, metabolic profiling analyses led to the discovery that TXNIP deficiency causes marked deficits in enzymes required for catabolism of branched chain amino acids, ketones, and lactate, along with more modest reductions in enzymes of β-oxidation and the tricarboxylic acid cycle. The decrements in enzyme activity were accompanied by comparable deficits in protein abundance without changes in mRNA expression, implying dysregulation of protein synthesis or stability. Considering that TXNIP expression increases in response to starvation, diabetes, and exercise, these findings point to a novel role for TXNIP in coordinating mitochondrial fuel switching in response to nutrient availability.

KEYWORDS:
Branched Chain Amino Acids; Diabetes; Energy Metabolism; Ketone Body Metabolism; Mitochondrial Metabolism; Redox; Skeletal Muscle Metabolism; Thioredoxin Interacting Protein

PMID:
24482226
PMCID:
PMC3961642
DOI:
10.1074/jbc.M113.511535
[Indexed for MEDLINE]
Free PMC Article

 

https://www.ncbi.nlm.nih.gov/pubmed/27572148

Hypertension. 2016 Nov;68(5):1245-1254. Epub 2016 Aug 29.
Mitochondrial Fission of Smooth Muscle Cells Is Involved in Artery Constriction.
Liu MY1, Jin J1, Li SL1, Yan J1, Zhen CL1, Gao JL1, Zhang YH1, Zhang YQ1, Shen X1, Zhang LS1, Wei YY1, Zhao Y1, Wang CG1, Bai YL1, Dong DL2.
Author information
Abstract
Mitochondria are dynamic organelles and continuously undergo fission and fusion processes. Mitochondrial fission is involved in multiple physiological or pathological processes, but the role of mitochondrial fission of smooth muscle cells in artery constriction is unknown. The role of mitochondrial fission of smooth muscle cells in arterial function was investigated by measuring the tension of rat mesenteric arteries and thoracic aorta and by evaluating mitochondrial fission, mitochondrial reactive oxygen species, and cytosolic [Ca2+]i in rat vascular smooth muscle cells. Mitochondrial fission inhibitors mdivi-1 and dynasore antagonized phenylephrine- and high K+-induced constriction of rat mesenteric arteries. Mdivi-1 relaxed phenylephrine-induced constriction, and mdivi-1 pretreatment prevented phenylephrine-induced constriction in mice, rat aorta, and human mesenteric arteries. Phenylephrine- and high K+-induced increase of mitochondrial fission in smooth muscle cells of rat aorta and the increase was inhibited by mdivi-1. Mdivi-1 inhibited high K+-induced increases of mitochondrial fission, mitochondrial reactive oxygen species, and cytosolic [Ca2+]i in rat vascular smooth muscle cells. Prechelation of cytosolic Ca2+ prevented high K+-induced cytosolic [Ca2+]i increase, mitochondrial fission, and mitochondrial reactive oxygen species overproduction. Mitochondria-targeted antioxidant mito-TEMPO antagonized phenylephrine- and high K+-induced constriction of rat mesenteric arteries. Nitroglycerin and ROCK (Rho-associated protein kinase) inhibitor Y27632, the 2 vasodilators with different vasorelaxant mechanisms, relaxed high K+-induced vasoconstriction and inhibited high K+-induced mitochondrial fission. In conclusion, the mitochondrial fission of smooth muscle cells is involved in artery constriction.

© 2016 American Heart Association, Inc.

KEYWORDS:
arteries; hypertension; mitochondrial dynamics; myocytes, smooth muscle; vasodilation

PMID:
27572148
DOI:
10.1161/HYPERTENSIONAHA.116.07974

 

https://www.ncbi.nlm.nih.gov/pubmed/28540168

Acta Pharm Sin B. 2017 May;7(3):319-325. doi: 10.1016/j.apsb.2016.12.009. Epub 2017 Mar 3.
Arterial relaxation is coupled to inhibition of mitochondrial fission in arterial smooth muscle cells: comparison of vasorelaxant effects of verapamil and phentolamine.
Jin J1,2, Shen X1,2, Tai Y1,2, Li S1,2, Liu M1,2, Zhen C1,2, Xuan X1,2, Zhang X1,2, Hu N1,2, Zhang X1,2, Dong D1,2.
Author information
Abstract
Mitochondria are morphologically dynamic organelles which undergo fission and fusion processes. Our previous study found that arterial constriction was always accompanied by increased mitochondrial fission in smooth muscle cells, whereas inhibition of mitochondrial fission in smooth muscle cells was associated with arterial relaxation. Here, we used the typical vasorelaxants, verapamil and phentolamine, to further confirm the coupling between arterial constriction and mitochondrial fission in rat aorta. Results showed that phentolamine but not verapamil induced vasorelaxation in phenylephrine (PE)-induced rat thoracic aorta constriction. Verapamil, but not phentolamine, induced vasorelaxation in high K+ (KPSS)-induced rat thoracic aorta constriction. Pre-treatment with phentolamine prevented PE- but not KPSS-induced aorta constriction and pre-treatment with verapamil prevented both PE- and KPSS-induced aorta constriction. Transmission electron microscopy (TEM) results showed that verapamil but not phentolamine inhibited KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells, and verapamil prevented both PE- and KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells. Verapamil inhibited KPSS-induced excessive mitochondrial fission in cultured vascular smooth muscle cells (A10). These results further demonstrate that arterial relaxation is coupled to inhibition of mitochondrial fission in arterial smooth muscle cells.

KEYWORDS:
Artery; Mitochondrial fission; Phentolamine; Vasorelaxation; Verapamil

PMID:
28540168
PMCID:
PMC5430753
DOI:
10.1016/j.apsb.2016.12.009
Free PMC Article

 

I’ve just thought why aren’t Prusty, Davis, others testing mdivi-1, a small molecule inhibitor of mitochondrial fission (Drp-1 dependent) that also crosses the BBB, with ME/CFS cells to further understand if mitochondrial fission/fragmentation are indeed playing a significant metabolic role? And testing it with on the nanoneedle as well?

 

Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis. Li et al. J Neuroinflammation 2019

 

Bhupesh K Prusty has shared on twitter...

https://twitter.com/user/status/1591062181675761664


To discuss Prusty's work go to this thread where the tweet has also been posted:
Research news from Bhupesh Prusty