Mitochondria–Lysosome Crosstalk: From Physiology to Neurodegeneration

Deus, Cláudia M.; Yambire, King Faisal; Oliveira, Paulo J.; Raimundo, Nuno

doi:10.1016/j.molmed.2019.10.009

Cited by 205 publications

(176 citation statements)

References 153 publications

(215 reference statements)

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“…& P < 0.05 and && P < 0.01 versus the rapamycin group. triggers program that result in the elimination of the defective mitochondria, first by promoting mitophagy, then by ensuring that the capacity for autophagosome degradation is increased by building more lysosomes (Deus et al, 2020). Our results suggested that H/R stimulation leads to defective mitophagy concurrently with cell injury and death, evidenced as reduced cell viability, increased expression of cleaved caspase 3, and apoptosis.…”

Section: Discussionmentioning

confidence: 62%

Ferulic Acid Attenuates Hypoxia/Reoxygenation Injury by Suppressing Mitophagy Through the PINK1/Parkin Signaling Pathway in H9c2 Cells

et al. 2020

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Ferulic acid protects against cardiac injury by scavenging free radicals. However, the role of mitophagy in ferulic acid-induced cardioprotection remains obscure. In the present study, H9c2 cells were exposed to hypoxia/reoxygenation and ferulic acid treatment during hypoxia. We illustrated the impact of ferulic acid on oxidative damage in H9c2 cells. Our results showed that ferulic acid significantly attenuated apoptosis induced by hypoxia/reoxygenation injury and reduced mitochondrial dysfunction, evidenced by a decline in the overproduction of reactive oxygen species and ATP depletion and recovery of the membrane potential. We also found that mitophagy, a selective form of autophagy, was excessively activated in H9c2 cells subjected to hypoxia/reoxygenation. Ferulic acid reduced the binding of mitochondria to lysosomes, down-regulated the PINK1/Parkin pathway, and was accompanied by increased p62 and decreased LC3-II/LC3-I levels. Ferulic acid also antagonistically reduced the activation of mitophagy by rapamycin. These findings suggest that ferulic acid may protect H9c2 cells against ischemia/reperfusion injury by suppressing PINK1/Parkin-dependent mitophagy. Accordingly, our findings may provide a potential target and powerful reference for ferulic acid in clinical prevention and treatment of hypoxia/reoxygenation injury.

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Section: Discussionmentioning

confidence: 62%

Ferulic Acid Attenuates Hypoxia/Reoxygenation Injury by Suppressing Mitophagy Through the PINK1/Parkin Signaling Pathway in H9c2 Cells

et al. 2020

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“…Therefore, we consider that mitochondrial fragmentation keeps low metabolism levels to reduce cytotoxicity in MD fibroblasts. Mitochondrial fission promotes clearance of damaged mitochondria through a form of autophagy known as mitophagy [42], whereas perturbation of mitochondrial dynamics has been shown to cause lysosomal dysfunction and autophagy impairment [43], and chronic mitochondrial defects trigger general impairment of autophagy and lysosomes to avoid complete degradation of the mitochondrial network [44,45]. Drp1 knockdown or treatment with bafilomycin A1, an autophagic flux inhibitor, significantly increased the amount of mitochondria in MD fibroblasts (Supplementary Figure S2A-C).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

et al. 2020

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Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.Biomolecules 2020, 10, 450 2 of 13 respiratory chain complexes [7]. However, in multiple cases, the exact genetic cause of Leigh syndrome remains unknown [8]. Currently, there is no cure or effective treatment for MD, but recent research has shown the potential benefits of some approaches, at least in preclinical in vivo models [9][10][11]. Many researchers assume that both bulk and mitochondrial autophagy play protective roles in MD because the accumulation of damaged mitochondria and other toxic aggregates causes deterioration of the pathophysiology of the cell [12]. Preclinical studies suggest that a potential therapeutic target of disease progression is the mammalian target of rapamycin (mTOR) pathway, a biological route fundamental for regulating cell metabolism and physiology [13]. In mice models of Leigh syndrome, treatment with rapamycin, an mTOR inhibitor, extended lifespan and reduced disease progression and severity [14]. Civiletto et al. provided evidence that rapamycin induces improvements in mitochondrial function and ultrastructure, indicating powerful clearance of dysfunctional organelles via activation of autophagic flux in skeletal muscle.Mitochondria are highly dynamic organelles that continuously fuse, divide, and move, and mitochondrial function is controlled and maintained by these morphologic changes. Mitochondrial fission is specifically mediated by dynamin-related guanosine triphosphatase (GTPase) protein 1 (Drp1); in addition, dynamin-related GTPases mitofusin (Mfn) and optic atrophy 1 (OPA1) are associated with the outer and inner mitochondrial membranes, respectively, and mediate fusion of these membranes [15][16][17][18][19]. The most direct consequence of mitochondrial division and fusion is the change in size of the mitochondria [20][21][22]. Mitochondrial fission via Drp1 has been thought to regulate mitophagy by dividing mitochondria into fragments suitable for autophagosome engulfment [23][24][25] and/or separating damaged subdomains of mitochondria for elimination [26]. Mitochondrial fusion enables efficient mixing of m...

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“…In addition to their involvement in the catabolism and subsequent recycling of biomolecules, lysosomes coordinate a broad range of intracellular signaling pathways, ranging from mTOR, AMPK, Calcineurin, AKT and ERK1/2, all of which contribute to cancer progression (19,20). Importantly, lysosomal function is essential for mitochondrial function and homeostasis, consistent with the role of these two organelles in promoting malignancies (21)(22)(23). For instance, the lysosomal biogenesis regulator transcription factor EB (TFEB) is essential for mitochondrial biogenesis, respiratory chain complex activities, and ATP production (24,25), while the endolysosomal Rabs play a central role in mitochondrial oxygen consumption, cytochrome-C release during oxidative stress, and mitophagy (26,27).…”

Section: Introductionmentioning

confidence: 84%

The lysosomal TRPML1 channel promotes breast cancer survival by supporting mitochondrial function and cellular metabolism

Almasi

Kennedy

Yoast

et al. 2020

Preprint

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Triple-negative breast cancer (TNBC) is an aggressive subtype representing approximately 10%-20% of breast cancers and lacking effective therapies. TRPML1, which is a lysosomal Ca2+ release channel upregulated in TNBC, promotes TNBC tumor growth. Here we show a novel crosstalk between lysosomes and mitochondria mediated by TRPML1 in TNBC. TRPML1 is required for the maintenance of mitochondrial function and reactive oxygen species (ROS) homeostasis. TRPML1 knockdown inhibits TNBC mitochondrial respiration, glycolysis and ATP production, leading to reduced proliferation, promotion of cell cycle arrest and apoptosis with enhanced global and mitochondrial ROS. Further, TRPML1 downregulation enhances the cytotoxic effect of Doxorubicin in TNBC cells. Our data reveal a hitherto unknown link between lysosomal TRPML1 channels and mitochondrial metabolism and suggest that TRPML1 inhibition in combination with established chemotherapies could be an effective strategy against TNBC tumors.

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Mitochondria–Lysosome Crosstalk: From Physiology to Neurodegeneration

Cited by 205 publications

References 153 publications

Ferulic Acid Attenuates Hypoxia/Reoxygenation Injury by Suppressing Mitophagy Through the PINK1/Parkin Signaling Pathway in H9c2 Cells

Ferulic Acid Attenuates Hypoxia/Reoxygenation Injury by Suppressing Mitophagy Through the PINK1/Parkin Signaling Pathway in H9c2 Cells

Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

The lysosomal TRPML1 channel promotes breast cancer survival by supporting mitochondrial function and cellular metabolism

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