Mitochondrial Dysfunction and Aging: Insights from the Analysis of Extracellular Vesicles

Abstract

The progressive decline of cell function and integrity, manifesting clinically as increased vulnerability to adverse outcomes and death, is core to biological aging. Mitochondrial dysfunction, oxidative stress, altered intercellular communication (including chronic low-grade inflammation), genomic instability, telomere attrition, loss of proteostasis, altered nutrient sensing, epigenetic alterations, and stem cell exhaustion have been proposed as hallmarks of aging. These “aging pillars” are not mutually exclusive, making the matter intricate and leaving numerous unanswered questions. The characterization of circulating extracellular vesicles (EVs) has recently allowed specific secretory phenotypes associated with aging to be identified. As such, EVs may serve as novel biomarkers for capturing the complexity of aging. Besides the mitochondrial–lysosomal axis, EV trafficking has been proposed as an additional layer in mitochondrial quality control. Indeed, disruption of the mitochondrial–lysosomal axis coupled with abnormal EV secretion may play a role in the pathogenesis of aging and several disease conditions. Here, we discuss (1) the mechanisms of EV generation; (2) the relationship between the mitochondrial–lysosomal axis and EV trafficking in the setting of mitochondrial quality control; and (3) the prospect of using EVs as aging biomarkers and as delivery systems for therapeutics against age-related conditions.

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

“…Fine-tuning of MQC processes is key to preserving a functional mitochondrial network within the cell [16]. Mitochondrial fission regulates the rate of mitochondrial biogenesis and mitochondrial DNA (mtDNA) synthesis [25,26] under the control of GTPase dynamin-related protein 1 (DRP1), fission protein 1 (FIS1), dynamin 2, and actin [24,[27][28][29].…”

“…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, biogenesis, and autophagy [16]. While continuous cycles of fusion and fission preserve mitochondrial shape and dilute damage along the network [17] mitochondrial hyper-fission segregates damaged or unnecessary organelles from the network [17].…”

“…Damaged mitochondrial components may follow an alternative degradative route that operates through the release of specialized extracellular vesicles (EVs), namely mitochondrial derived vesicles (MDVs), before whole-sale organelle degradation is triggered. This pathway involving mitochondrial-lysosomal crosstalk has been proposed as an additional layer of MQC [20].Dysregulation of mitophagy and disruption of the mitochondrial-lysosomal axis coupled with abnormal EV secretion have been implicated as mechanisms in the aging process and related disease conditions [16,21]. More specifically, the garbage theory of aging poses that damaged mitochondria, protein aggregates, and lipofuscin accumulate as a result of inefficient cellular quality control [22].…”

“…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, biogenesis, and autophagy [16]. While continuous cycles of fusion and fission preserve mitochondrial shape and dilute damage along the network [17] mitochondrial hyper-fission segregates damaged or unnecessary organelles from the network [17].…”

“…Dysregulation of mitophagy and disruption of the mitochondrial-lysosomal axis coupled with abnormal EV secretion have been implicated as mechanisms in the aging process and related disease conditions [16,21]. More specifically, the garbage theory of aging poses that damaged mitochondria, protein aggregates, and lipofuscin accumulate as a result of inefficient cellular quality control [22].…”