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A voltage-dependent K⁺ channel in the lysosome is required for refilling lysosomal Ca²⁺ stores.

ABSTRACT: The resting membrane potential (??) of the cell is negative on the cytosolic side and determined primarily by the plasma membrane's selective permeability to K⁺ We show that lysosomal ?? is set by lysosomal membrane permeabilities to Na⁺ and H⁺, but not K⁺, and is positive on the cytosolic side. An increase in juxta-lysosomal Ca²⁺ rapidly reversed lysosomal ?? by activating a large voltage-dependent and K⁺-selective conductance (LysoK_VCa). LysoK_VCa is encoded molecularly by SLO1 proteins known for forming plasma membrane BK channels. Opening of single LysoK_VCa channels is sufficient to cause the rapid, striking changes in lysosomal ??. Lysosomal Ca²⁺ stores may be refilled from endoplasmic reticulum (ER) Ca²⁺ via ER-lysosome membrane contact sites. We propose that LysoK_VCa serves as the perilysosomal Ca²⁺ effector to prime lysosomes for the refilling process. Consistently, genetic ablation or pharmacological inhibition of LysoK_VCa, or abolition of its Ca²⁺ sensitivity, blocks refilling and maintenance of lysosomal Ca²⁺ stores, resulting in lysosomal cholesterol accumulation and a lysosome storage phenotype.

SUBMITTER: Wang W

PROVIDER: S-EPMC5461029 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A voltage-dependent K+ channel in the lysosome is required for refilling lysosomal Ca2+ stores.

Wang Wuyang W Zhang Xiaoli X Gao Qiong Q Lawas Maria M Yu Lu L Cheng Xiping X Gu Mingxue M Sahoo Nirakar N Li Xinran X Li Ping P Ireland Stephen S Meredith Andrea A Xu Haoxing H

The Journal of cell biology 20170503 6

The resting membrane potential (Δψ) of the cell is negative on the cytosolic side and determined primarily by the plasma membrane's selective permeability to K+ We show that lysosomal Δψ is set by lysosomal membrane permeabilities to Na+ and H+, but not K+, and is positive on the cytosolic side. An increase in juxta-lysosomal Ca2+ rapidly reversed lysosomal Δψ by activating a large voltage-dependent and K+-selective conductance (L ...[more]

PMID: 28468834

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Project description:Mitochondria critically regulate a range of cellular processes including bioenergetics, cellular metabolism, apoptosis, and cellular Ca2+ signaling. The voltage-dependent anion channel (VDAC) functions as a passageway for the exchange of ions, including Ca2+, across the outer mitochondrial membrane. In cardiomyocytes, genetic or pharmacological activation of isoform 2 of VDAC (VDAC2) effectively potentiates mitochondrial Ca2+ uptake and suppresses Ca2+ overload-induced arrhythmogenic events. However, molecular mechanisms by which VDAC2 controls mitochondrial Ca2+ transport and thereby influences cardiac rhythmicity remain elusive. Vertebrates express three highly homologous VDAC isoforms. Here, we used the zebrafish tremblor/ncx1h mutant to dissect the isoform-specific roles of VDAC proteins in Ca2+ handling. We found that overexpression of VDAC1 or VDAC2, but not VDAC3, suppresses the fibrillation-like phenotype in zebrafish tremblor/ncx1h mutants. A chimeric approach showed that moieties in the N-terminal half of VDAC are responsible for their divergent functions in cardiac biology. Phylogenetic analysis further revealed that a glutamate at position 73, which was previously described to be an important regulator of VDAC function, is sevolutionarily conserved in VDAC1 and VDAC2, whereas a glutamine occupies position 73 (Q73) of VDAC3. To investigate whether E73/Q73 determines VDAC isoform-specific anti-arrhythmic effect, we mutated E73 to Q in VDAC2 (VDAC2E73Q) and Q73 to E in VDAC3 (VDAC3Q73E). Interestingly, VDAC2E73Q failed to restore rhythmic cardiac contractions in ncx1 deficient hearts, while the Q73E conversion induced a gain of function in VDAC3. In HL-1 cardiomyocytes, VDAC2 knockdown diminished the transfer of Ca2+ from the SR into mitochondria and overexpression of VDAC2 or VDAC3Q73E restored SR-mitochondrial Ca2+ transfer in VDAC2 deficient HL-1 cells, whereas this rescue effect was absent for VDAC3 and drastically compromised for VDAC2E73Q. Collectively, our findings demonstrate a critical role for the evolutionary conserved E73 in determining the anti-arrhythmic effect of VDAC isoforms through modulating Ca2+ cross-talk between the SR and mitochondria in cardiomyocytes.

Dataset Information

A voltage-dependent K⁺ channel in the lysosome is required for refilling lysosomal Ca²⁺ stores.

Publications

A voltage-dependent K<sup>+</sup> channel in the lysosome is required for refilling lysosomal Ca<sup>2+</sup> stores.

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