bims-mikwok 2022-01-16 papers

Issue of 2022‒01‒16
six papers selected by
Avinash N. Mukkala, University of Toronto

Biochimie. 2022 Jan 10. pii: S0300-9084(22)00002-5. [Epub ahead of print]

Therapeutic applications of mitochondrial transplantation.

This review aims to make a framework of exogenous healthy mitochondrial transplantation and to assemble present information for improving new therapeutic applications in a variety of diseases. Recently, the significance of mitochondrial transplantation has been emphasized in a variety of mitochondrial dysfunction-related diseases such as neurodegenerative diseases, toxic injury, ischemia, cardiovascular diseases. We describe the natural mitochondrial transfer mechanisms (ie. TNT, EVs, mitochondrial dynamics), mitochondrial isolation process for transplantation (ie. source of mitochondria, requirements for successful isolation), mitochondrial transplantation methods (in vivo, in vitro), the effects and limitations of mitochondrial transplantation. Since mitochondrial transplantation is seen as an innovative potential treatment for diseases that can not be treated at the desired level, we expect to represent how the mitochondrial transplantation methods can be used in different diseases.

Keywords: Mitochondria dysfunction; Mitochondrial dynamics; Mitochondrial isolation; Mitochondrial transplantation

DOI: https://doi.org/10.1016/j.biochi.2022.01.002

Mitochondrion. 2022 Jan 06. pii: S1567-7249(22)00001-0. [Epub ahead of print]63 23-31

Mitochondrial repair as potential pharmacological target in cerebral ischemia.

Ms Mandeep Kaur, Dr Saurabh Sharma.

Cerebral ischemia and its consequences like transient ischemic attack, aneurysm and stroke are the common and devastating conditions which remain the leading cause of mortality after coronary heart disease in developed countries and are the greatest cause of disability, leaving 50% of survivors permanently disabled. Despite recognition of risk factors and mechanisms involved in the pathology of the disease, treatment of ischemic disorders is limited to thrombolytic drugs like recombinant tissue plasminogen activator (rt-PA) and clinical rendition of the neuroprotective agents have not been so successful. Recent studies evidenced the role of mitochondrial dysfunction in neuronal damage that occurred after cerebral ischemia. This review article will focus on the various fundamental mechanisms responsible for neuronal damage because of mitochondrial dysfunction including cell signaling pathways, autophagy, apoptosis/necrosis, generation of reactive oxygen species, calcium overload, the opening of membrane permeability transition pore (mPTP), mitochondrial dynamics and biogenesis. Recent studies have concerned the significant role of mitochondrial biogenesis in mitochondrial repair and transfer of healthy mitochondria from astrocytes to the damaged neurons, providing neuroprotection and neural recovery following ischemia. Novel and influential studies have evidenced the significant role of mitochondria transfer and mitochondrial transplantation in reviving cell energy and in replacement of impaired or dysfunctional mitochondria with healthy mitochondria after ischemic episode. This review article will focus on recent advances in mitochondrial interventions and exogenous therapeutic modalities like mitochondria transfer technique, employment of stem cells, mitochondrial transplantation, miRNA inhibition and mitochondrial-targeted Sirtuin1 activator for designing novel and promising treatment for cerebral ischemia induced pathological states.

Keywords: Cerebral ischemia; Mitochondrial transfer; Mitochondrial transplantation; Mitochondrial dysfunction; Mitophagy; Reactive oxygen species; miRNA inhibition

DOI: https://doi.org/10.1016/j.mito.2022.01.001

Cells. 2021 Dec 23. pii: 38. [Epub ahead of print]11(1):

Molecular Mechanisms and Regulation of Mammalian Mitophagy.

Vinay Choubey, Akbar Zeb, Allen Kaasik.

Mitochondria in the cell are the center for energy production, essential biomolecule synthesis, and cell fate determination. Moreover, the mitochondrial functional versatility enables cells to adapt to the changes in cellular environment and various stresses. In the process of discharging its cellular duties, mitochondria face multiple types of challenges, such as oxidative stress, protein-related challenges (import, folding, and degradation) and mitochondrial DNA damage. They mitigate all these challenges with robust quality control mechanisms which include antioxidant defenses, proteostasis systems (chaperones and proteases) and mitochondrial biogenesis. Failure of these quality control mechanisms leaves mitochondria as terminally damaged, which then have to be promptly cleared from the cells before they become a threat to cell survival. Such damaged mitochondria are degraded by a selective form of autophagy called mitophagy. Rigorous research in the field has identified multiple types of mitophagy processes based on targeting signals on damaged or superfluous mitochondria. In this review, we provide an in-depth overview of mammalian mitophagy and its importance in human health and diseases. We also attempted to highlight the future area of investigation in the field of mitophagy.

Keywords: BNIP3; FUNDC1; PARKIN; PINK1; Parkinson’s disease; autophagy; cardiolipin; mitophagy; quality control

DOI: https://doi.org/10.3390/cells11010038

JCI Insight. 2022 Jan 11. pii: e150041. [Epub ahead of print]

Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.

Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H Knudsen, Mayer M Chalom, Kyle A Starost, Israel C Nnah, Chih-Hao Lee.

Mitophagy and mitochondrial integrated stress response (ISR) are two primary protective mechanisms to maintain functional mitochondria. Whether these two processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 over-expression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD fed mice. RNA-seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I stimulated genes through Atf5, which inhibits the transactivation activity of Irf3 known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 over-expression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.

Keywords: Glucose metabolism; Metabolism; Mitochondria; Obesity

DOI: https://doi.org/10.1172/jci.insight.150041

iScience. 2022 Jan 21. 25(1): 103650

Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase.

Evgeny Shlevkov, Paramasivam Murugan, Dan Montagna, Eric Stefan, Adelajda Hadzipasic, James S Harvey, P Rajesh Kumar, Sonya Entova, Nupur Bansal, Shari Bickford, Lai-Yee Wong, Warren D Hirst, Andreas Weihofen, Laura F Silvian.

Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. Here we identify several compounds that enhance the activity of wildtype Parkin in the presence of phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these compounds activate Parkin in a series of biochemical assays, they do not act by thermally destabilizing Parkin and fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that in the context of the cellular milieu the therapeutic window to pharmacologically activate Parkin is very narrow.

Keywords: Biochemistry; Biochemistry Applications; Chemistry

DOI: https://doi.org/10.1016/j.isci.2021.103650

EMBO J. 2022 Jan 13. e108587

DRP1 interacts directly with BAX to induce its activation and apoptosis.

Andreas Jenner, Aida Peña-Blanco, Raquel Salvador-Gallego, Begoña Ugarte-Uribe, Cristiana Zollo, Tariq Ganief, Jan Bierlmeier, Marcus Mund, Jason E Lee, Jonas Ries, Dirk Schwarzer, Boris Macek, Ana J Garcia-Saez.

The apoptotic executioner protein BAX and the dynamin-like protein DRP1 co-localize at mitochondria during apoptosis to mediate mitochondrial permeabilization and fragmentation. However, the molecular basis and functional consequences of this interplay remain unknown. Here, we show that BAX and DRP1 physically interact, and that this interaction is enhanced during apoptosis. Complex formation between BAX and DRP1 occurs exclusively in the membrane environment and requires the BAX N-terminal region, but also involves several other BAX surfaces. Furthermore, the association between BAX and DRP1 enhances the membrane activity of both proteins. Forced dimerization of BAX and DRP1 triggers their activation and translocation to mitochondria, where they induce mitochondrial remodeling and permeabilization to cause apoptosis even in the absence of apoptotic triggers. Based on this, we propose that DRP1 can promote apoptosis by acting as noncanonical direct activator of BAX through physical contacts with its N-terminal region.

Keywords: BCL-2 proteins; fluorescence correlation spectroscopy; membrane protein complex; mitochondrial division; super-resolution microscopy

DOI: https://doi.org/10.15252/embj.2021108587