Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells

Of the many crucial functions of the ER, homeostasis of physiological calcium increase is critical for signaling. Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR.

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Faculty Opinions recommendation of Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1028188.341132 ◽

2005 ◽

Author(s):

Brigitte Huber

Keyword(s):

Plasma Membrane ◽

Membrane Repair ◽

Plasma Membrane Repair ◽

Induction Of Apoptosis ◽

Ctl Induction

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Plasma membrane repairs by small GTPase Rab3a

The Journal of Cell Biology ◽

10.1083/jcb.201606006 ◽

2016 ◽

Vol 213 (6) ◽

pp. 613-615 ◽

Cited By ~ 2

Author(s):

Camilla Raiborg ◽

Harald Stenmark

Keyword(s):

Plasma Membrane ◽

Small Gtpase ◽

Membrane Repair ◽

Cell Biol ◽

Plasma Membrane Repair

Lysosomes fuse with the plasma membrane to help repair membrane lesions, but how they are positioned close to these lesions is not fully understood. Now, Encarnação et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201511093) demonstrate that the lysosomal GTPase Rab3a and its effectors orchestrate lysosome positioning and plasma membrane repair.

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Mitochondrial fragmentation enables localized signaling required for cell repair

The Journal of Cell Biology ◽

10.1083/jcb.201909154 ◽

2020 ◽

Vol 219 (5) ◽

Cited By ~ 3

Author(s):

Adam Horn ◽

Shreya Raavicharla ◽

Sonna Shah ◽

Dan Cox ◽

Jyoti K. Jaiswal

Keyword(s):

Plasma Membrane ◽

Calcium Influx ◽

Cell Damage ◽

Mitochondrial Fission ◽

Adaptor Protein ◽

Mitochondrial Fragmentation ◽

Membrane Repair ◽

Membrane Injury ◽

Mitochondrial Signaling ◽

Plasma Membrane Repair

Plasma membrane injury can cause lethal influx of calcium, but cells survive by mounting a polarized repair response targeted to the wound site. Mitochondrial signaling within seconds after injury enables this response. However, as mitochondria are distributed throughout the cell in an interconnected network, it is unclear how they generate a spatially restricted signal to repair the plasma membrane wound. Here we show that calcium influx and Drp1-mediated, rapid mitochondrial fission at the injury site help polarize the repair response. Fission of injury-proximal mitochondria allows for greater amplitude and duration of calcium increase in these mitochondria, allowing them to generate local redox signaling required for plasma membrane repair. Drp1 knockout cells and patient cells lacking the Drp1 adaptor protein MiD49 fail to undergo injury-triggered mitochondrial fission, preventing polarized mitochondrial calcium increase and plasma membrane repair. Although mitochondrial fission is considered to be an indicator of cell damage and death, our findings identify that mitochondrial fission generates localized signaling required for cell survival.

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