Polybrene induces neural degeneration by bidirectional Ca2+ influx-dependent mitochondrial and ER-mitochondrial dynamics

Cell Death & Disease
Fei-Xiang BaoXing-Guo Liu

Abstract

Hexadimethrine bromide (Polybrene) was once used clinically as a heparin neutralizer and has recently found use as a promoter in virus-mediated gene therapy trials and gene transfer in research. However, the potential for tissue-specific toxicity of polybrene at low doses has been ignored so far. Here, we found that after intracerebroventricular (ICV) polybrene injection, mice showed disability of movement accompanied neural death and gliosis in brain, and in human neurons, polybrene induces concentration-dependent neuritic beading and fragmentation. Mechanistically, polybrene induces a rapid voltage-dependent calcium channel (VDCC)-mediated influx of extracellular Ca2+. The elevated cytoplasmic Ca2+ activates DRP1, which leads to mitochondrial fragmentation and metabolic dysfunction. At the same time, Ca2+ influx induces endoplasmic reticulum (ER) fragmentation and tightened associations between ER and mitochondria, which makes mitochondria prone to Ca2+ overloading and ensuing permeability transition. These results reveal an unexpected neuronal toxicity of polybrene, wherein Ca2+ influx serves as a regulator for both mitochondrial dynamics and ER-mitochondrial remodeling.

References

Oct 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·N FerryJ M Heard
Jan 1, 1990·Annual Review of Neuroscience·D W Choi, S M Rothman
Dec 6, 1996·Neuroscience Letters·M J HurleyK Uchida
Jan 6, 1999·Biophysical Journal·R C Scaduto, L W Grotyohann
Jan 5, 2000·Physiological Reviews·D G Nicholls, S L Budd
Apr 12, 2000·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·R Sattler, M Tymianski
May 23, 2002·Biochimie·Hans Friberg, Tadeusz Wieloch
Feb 11, 2003·Advances in Experimental Medicine and Biology·Thomas GillessenStuart A Lipton
May 24, 2003·Trends in Molecular Medicine·Mark P Mattson, Guido Kroemer
Feb 8, 1958·Journal of the American Medical Association·W A WEISSA E OSTERBERG
May 1, 1965·The Journal of Surgical Research·H T RANSDELLP B BARTON
Mar 26, 2004·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Marta Bellodi-PrivatoNicolas Ferry
Jul 19, 2005·Nature Reviews. Molecular Cell Biology·Richard J Youle, Mariusz Karbowski
Jan 18, 2006·Human Gene Therapy·Liang-Fong WongNicholas D Mazarakis
Jul 29, 2006·The EMBO Journal·Mark J BarsoumElla Bossy-Wetzel
Sep 20, 2006·The Journal of Cell Biology·György CsordásGyörgy Hajnóczky
Dec 19, 2006·Neurobiology of Aging·J AbrahamR W Johnson
Dec 21, 2006·The Journal of Cell Biology·György SzabadkaiRosario Rizzuto
May 9, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Craig Press, Jeffrey Milbrandt
Oct 8, 2008·Proceedings of the National Academy of Sciences of the United States of America·G M CereghettiL Scorrano
Dec 5, 2008·Nature·Olga Martins de Brito, Luca Scorrano
Jan 16, 2009·Trends in Cell Biology·Teruo HayashiTsung-Ping Su
May 8, 2009·Molecular Neurodegeneration·Philippe MarambaudValérie Vingtdeux
May 16, 2009·Current Topics in Medicinal Chemistry·Takashi Yamamoto, Akira Takahara
Jun 27, 2009·Science·Benoît KornmannPeter Walter
May 9, 2012·Handbook of Experimental Pharmacology·Menaka Pai, Mark A Crowther
Sep 21, 2012·Nature Reviews. Molecular Cell Biology·Ashley A Rowland, Gia K Voeltz
Jan 4, 2013·Molecular Biology of the Cell·Oliver C LosónDavid C Chan

❮ Previous
Next ❯

Citations

Jul 1, 2020·Journal of Molecular Cell Biology·Yang LiuXingguo Liu

❮ Previous
Next ❯

Methods Mentioned

BETA
Fluorescence
glycosis
protein assay

Software Mentioned

ImageJ
Zeiss
Graph Pad Prism
ZEN

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.