Loss of Mitochondrial Function Impairs Lysosomes

Abstract

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model

“…Consistent with oxidative stress reducing lysosomal function [5,6], 6-OHDA treatment of neuronal PC12 cells inhibited autophagic flux as measured by the increase in p62 levels despite LC3-II levels similar to control cells (Figure 5A,B). Importantly, OLE did not further modulate the decrease in autophagic flux caused by 6-OHDA (OLE + 6-OHDA).…”

Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis

“…The importance of avoiding excessive lysosomal biogenesis is underscored by the repression of the transcript levels of lysosomal genes under chronic mitochondrial stress. Interestingly, mitochondrial malfunction seems to be associated with lysosomal impairments, both in acute (TFAM−/− T cells upon activation)14 and chronic stress (e.g., OPA1−/−, AIF−/− MEFs)26, characterized by enlarged dysfunctional lysosomes akin to the saturated organelles observed in lysosomal storage diseases.…”

“…( D ) Relative transcript levels of LAMP1, GAA, CTSD and CTSF in fibroblasts from patients with mutations in respiratory chain complex I subunits (red bars) and control individuals (white), normalized to GAPDH. Patient 1 presents a mutation in the NDUFV1 subunit26 and patient two has a mutation in the NDUFV2 subunit27. The bars represent average and S.E.M.…”

Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

“…Because a failure in the functioning of lysosomes can be induced in various settings, including genetic factors 35, 36 , oxidative stress 37 , and mitochondrial dysfunction 38 , increasing evidence indicates that lysosomal impairment is associated with activation of inflammatory signals 9, 39 . For instance, impairment of the autophagy–lysosome pathway causes dysfunction of mitochondrial clearance, which results in generation of ROS and a release of mitochondrial DNA 9 .…”