Dr. Dimitri Krainc Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1
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Dr. Dimitri Krainc Published in the Proceedings of the National Academy of the Sciences

Dr. Dimitri Krainc and his team also published a study in the Proceedings of the National Academy of the Sciences (PNAS) about how lysosomes transfer calcium to mitochondria. This is important because in many neurological disorders like Parkinson’s disease, the function, and activity of mitochondria are disrupted. This discovery provides a blueprint for boosting mitochondrial function for people with neurodegenerative diseases.

“The results from this study, as well as our previous work on mitochondria and lysosome crosstalk, are exciting because they suggest that by modulating lysosomal function, we may also be able to directly promote mitochondrial function,” says Dr. Dimitri Krainc, who is also director of Northwestern Medicine Simpson Querrey Center for Neurogenetics.

Significance

Mitochondria and lysosomes are critical for cellular homeostasis and defects in both organelles are observed in several diseases. Recently, contact sites between mitochondria and lysosomes were identified and found to modulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts have additional functions is unknown. Here, we identify a function of mitochondria–lysosome contacts in facilitating the direct transfer of calcium from lysosomes to mitochondria. Transfer of calcium at mitochondria–lysosome contacts is mediated by the lysosomal channel TRPML1 and is disrupted in mucolipidosis type IV, a lysosomal storage disorder caused by loss-of-function mutations in TRPML1. Calcium transfer from lysosomes to mitochondria at mitochondria–lysosome contacts thus presents an additional mechanism of intracellular calcium regulation that may further contribute to various disorders.

New Genetic Cause of Dystonia Revealed by Dimitri Krainc

Abstract

Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria–lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria–lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria–lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria–lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.

Dimitri Krainc, Northwestern Medicine Scientists Published in The Journal of Neuroscience

Interorganelle contact sites have become increasingly appreciated as essential regulators of cellular homeostasis. Contact sites, which form dynamically between two distinct organelles in close proximity, have been shown to have a variety of functions, including the ability to act as platforms for the direct transfer of ions, such as calcium (16). Recently, interorganelle contact sites between mitochondria and lysosomes were characterized, revealing a novel mechanism of cross-talk between the two organelles (718). Interestingly, both mitochondria and lysosomes are also important players in cellular homeostasis, including intracellular calcium dynamics (1922), and a number of diseases presenting with mitochondrial and lysosomal dysfunction also exhibit dysregulation of cellular calcium (2330). Although the calcium dynamics of mitochondria and lysosomes have previously been studied individually or in relation to other organelles (153132), whether mitochondria and lysosomes can interact directly to modulate their calcium states has not been elucidated. Mitochondria–lysosome contacts may thus enable the direct transfer of calcium between lysosomes and mitochondria and function as an additional pathway in regulating intracellular calcium homeostasis.

Transient receptor potential mucolipin 1 (TRPML1) is a lysosomal/late-endosomal cation channel that mediates lysosomal calcium efflux (3338) and function (3944), and dysfunction in TRPML1 has been associated with several mitochondrial defects (4546). In addition, loss-of-function mutations in TRPML1 cause mucolipidosis type IV (MLIV), an autosomal recessive lysosomal storage disorder characterized by psychomotor retardation, retinal degeneration, and developmental delay (334749), and which has been associated with various lysosomal and mitochondrial aberrations (45465054). However, whether TRPML1-mediated lysosomal calcium release modulates mitochondrial calcium dynamics via mitochondria–lysosome contact sites, and the role of mitochondria–lysosome contact site dysfunction in the pathophysiology of lysosomal storage disorders such as MLIV, has not previously been studied.

Using live-cell high spatial and temporal resolution microscopy, we show that TRPML1 lysosomal calcium release mediates the direct transfer of calcium into mitochondria. Calcium transfer from lysosomes to mitochondria is modulated by mitochondria–lysosome contact site tethering and is modulated by the outer and inner mitochondrial membrane proteins, voltage-dependent anion channel 1 (VDAC1) and mitochondrial calcium uniporter (MCU), respectively. Importantly, MLIV patient fibroblasts with loss of TRPML1 function exhibit disrupted mitochondria–lysosome contact site dynamics and contact-dependent calcium transfer, suggesting a potential contribution of dysregulated mitochondria–lysosome contact site dynamics in lysosomal storage disorders. Our results thus elucidate an additional mechanism for regulating intracellular calcium dynamics via mitochondria–lysosome contact sites, which are further implicated in disease pathophysiology.

Fig. 1.

Dr. Dimitri Krainc and his team also published a study in the Proceedings of the National Academy of the Sciences (PNAS)
TRPML1-mediated lysosomal calcium efflux leads to mitochondrial calcium influx. (A) Model of activation of lysosomal calcium release by TRPML1 agonist, ML-SA1, resulting in mitochondrial calcium influx at mitochondria–lysosome contacts. (B) Experimental design for the assessment of mitochondrial calcium responses (ΔF/F) to TRPML1 activation in live cells. (C and D) Mitochondrial calcium response in live HeLa cells expressing mitochondrial-matrix targeted calcium sensor, Mito-R-GECO1, in response to TRPML1 activation with ML-SA1 (31.25 µM) (yellow arrow) or control treatment (white arrow) at t = 0 s with representative time-lapse confocal images (Cn = 23 cells for ML-SA1, n = 20 cells for control) and mitochondrial calcium traces (ΔF/F) (Dn = 23 cells for ML-SA1, n = 20 cells for control). (Scale bars, 10 µm; 1 µm in zoom images.) (EG) Quantification of maximum mitochondrial calcium response (E), mean mitochondrial calcium response (F), and mitochondrial calcium response at 30, 60, 90, and 120 s (G) after TRPML1 activation with ML-SA1 (31.25 µM) or control treatment from confocal time-lapse images in C (n = 23 cells for ML-SA1, n = 20 cells for control). Data are means ± SEM (***P < 0.001, ****P < 0.0001, unpaired two-tailed t test).

Find out the results of the new study.

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