Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence

Park, Taezoon; Lee, Young‐Sam; Cho, Kyung A; Park, Sang Chul

doi:10.1016/j.arr.2018.08.003

Cited by 82 publications

(69 citation statements)

References 61 publications

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“…Such contact sites may therefore participate to some of the processes responsible for cell dyshomeostasis triggered by mitochondrial dysfunction. Hence, a deeper characterization of the structures ensuring inter-organelle crosstalk is crucial for a comprehensive assessment of mitochondrial dysfunction during aging [158]. This knowledge, in turn, is necessary to unveil strategic pathways that may be targeted for geroprotective interventions.…”

Section: Discussionmentioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca 2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition.Cells 2020, 9, 598 2 of 18 instability, telomere attrition, epigenetic alterations, deregulated nutrient sensing, and stem cell exhaustion [3]. According to the geroscience hypothesis, perturbations in these mechanisms increase the susceptibility to most chronic diseases, functional loss, and eventually, death [4]. Hence, these biologic pillars represent ideal targets for interventions to foster healthy aging [5,6].Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play sensor-transducer-effector roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness [7,8]. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules [9,10]. In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogene...

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Section: Discussionmentioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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“…Therefore, elevated nSMase activity partially accounts for increased EV production in senescent HDFs. Reactive oxygen species (ROS) levels increase in response to functional deterioration of senescent cell mitochondria [25,26]. nSMase is activated by ROS and can be inhibited by antioxidants [27,28].…”

Section: Enhanced Nsmase Activity In Senescent Hdfs Increases Ev Prodmentioning

confidence: 99%

“…MVBs are routed to either the plasma membrane or the lysosome, which results in ILV secretion as exosomes or their lysosomal degradation, respectively [3,26,29]. We hypothesized that lysosomal activity is related to the degree of exosome secretion.…”

Section: Dysfunctional Lysosomal Activity In Senescent Hdfs Is Relatementioning

confidence: 99%

“…We hypothesized that lysosomal activity is related to the degree of exosome secretion. In senescent cells, diminished lysosomal activity enhances a feedback loop between lysosomes and mitochondria by accumulating ROS [26] which, in turn, may affect nSMase activity. We measured lysosomal pH, one indicator of lysosome functionality, in young and senescent HDFs and found that it was higher in senescent than in young HDFs ( Figure 4A).…”

Section: Dysfunctional Lysosomal Activity In Senescent Hdfs Is Relatementioning

confidence: 99%

“…Senescent HDFs upregulated the lysosomal marker LAMP1 and the transcription factor TFEB, which controls lysosome biogenesis ( Figure 4B). Elevation of these proteins reflects a marked increase in lysosomal mass but diminished lysosomal activity [26,30]. KU60019, an ataxia telangiectasia mutated (ATM) inhibitor, recovers lysosome function by restoring ATM-blocked dimerization of ATPase subunits and alleviates senescence [31].…”

Section: Dysfunctional Lysosomal Activity In Senescent Hdfs Is Relatementioning

confidence: 99%

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Extracellular Vesicles Derived from Senescent Fibroblasts Attenuate the Dermal Effect on Keratinocyte Differentiation

Choi

Kil

Cho

2020

IJMS

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The skin is a multilayered and primary defensive organ. Intimate intercellular communication in the skin is necessary to ensure effective surveillance. Extracellular vesicles (EVs) are being explored for their involvement in intercellular skin communication. The aim of this study was to evaluate how human dermal fibroblasts (HDFs) accelerate EV production during senescence and the effects of senescence-associated EVs on epidermal homeostasis. Replicative senescent HDFs were assessed with senescence-associated β-galactosidase staining and the expression of senescence-related markers. Isolated EVs were characterized by dynamic light scattering and EV marker expression. EVs secreted from untreated young or senescent HDFs, or from those treated with a nSMase inhibitor, antioxidant, and lysosomal activity regulators, were determined by sandwich ELISA for CD81. Human epidermal keratinocytes were treated with young- and senescent HDF-derived EVs. Compared to young HDFs, senescent HDFs produced relatively high levels of EVs due to the increased nSMase activity, oxidative stress, and altered lysosomal activity. The nSMase inhibitor, antioxidant, and agents that recovered lysosomal activity reduced EV secretion in senescent HDFs. Relative to young HDF-derived EVs, senescent HDF-derived EVs were less supportive in keratinocyte differentiation and barrier function but increased proinflammatory cytokine IL-6 levels. Our study suggests that dermis-derived EVs may regulate epidermal homeostasis by reflecting cellular status, which provides insight as to how the dermis communicates with the epidermis and influences skin senescence.

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Programmable ROS‐Mediated Cancer Therapy via Magneto‐Inductions

Ning

Gao

et al. 2020

Advanced Science

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Reactive oxygen species (ROS), a group of oxygen derived radicals and derivatives, can induce cancer cell death via elevated oxidative stress. A spatiotemporal approach with safe and deep‐tissue penetration capabilities to elevate the intracellular ROS level is highly desirable for precise cancer treatment. Here, a mechanical‐thermal induction therapy (MTIT) strategy is developed for a programmable increase of ROS levels in cancer cells via assembly of magnetic nanocubes integrated with alternating magnetic fields. The magneto‐based mechanical and thermal stimuli can disrupt the lysosomes, which sequentially induce the dysfunction of mitochondria. Importantly, intracellular ROS concentrations are responsive to the magneto‐triggers and play a key role for synergistic cancer treatment. In vivo experiments reveal the effectiveness of MTIT for efficient eradication of glioma and breast cancer. By remote control of the force and heat using magnetic nanocubes, MTIT is a promising physical approach to trigger the biochemical responses for precise cancer treatment.

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Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence

Cited by 82 publications

References 61 publications

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Extracellular Vesicles Derived from Senescent Fibroblasts Attenuate the Dermal Effect on Keratinocyte Differentiation

Programmable ROS‐Mediated Cancer Therapy via Magneto‐Inductions

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