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

Abstract

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...

Biomarkers of Physical Frailty and Sarcopenia: Coming up to the Place?

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Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

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“…Metabolic alterations arising from deregulated nutrient sensing have been reported in the setting of neurodegeneration in conjunction with mitochondrial dysfunction and oxidative stress [24]. Indeed, mitochondrial homeostasis relies upon the integrity of intracellular organelle networks, inter-mitochondrial content exchange, and integration of metabolic signaling [22,24]. Via inter-mitochondrial junctions, adjacent organelles coordinate membrane cristae remodeling [25], while mitochondrial fusion allows matrix and intermembrane space content (i.e., proteins, mtDNA, and metabolites) to be mixed between organelles to avoid focal accumulation of damaged constituents [26].…”

Mitochondrial Protrusions in Neuronal Cells

“…Although the specific proteins being carried by these vesicles vary depending on the types of cellular stress ( Soubannier et al., 2012a , 2012b ; Sugiura et al., 2014 ), the vesicles mostly end up merging with lysosomes ( Soubannier et al., 2012a ; McLelland et al., 2014 ) or peroxisomes ( Braschi et al., 2010 ; Neuspiel et al., 2008 ), suggesting that their primary role is to remove and dispose of damaged mitochondrial proteins or small parts of the organelle. Because the cellular stresses that elicit the production of the mitochondrial vesicles are in general milder than the stresses that trigger mitophagy, it is believed that the mitochondrial vesicles provide a constant or early-step quality control mechanism for the mitochondria prior to mitophagy ( Cadete et al., 2016 ; Misgeld and Schwarz, 2017 ; Picca et al., 2020 ; Youle, 2019 ).…”