Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Abstract

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson’s disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species (ROS), all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality-control pathways such as the ubiquitin–proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

“…Approaches to improve the cellular environment, as can be achieved by hypoxic conditioning, are expected to represent a superior approach to target mitochondrial dysfunction in neurodegeneration [ 174 ] as compared to targeting specific downstream consequences of mitochondrial damage, in approaches targeting, for example, ROS or ATP levels in HD [ 215 , 216 ]. Hypoxic conditioning by itself is limited in many regards; age [ 217 ] and disease may blunt adaptive physiological and molecular adaptations and the selection of the hypoxic dose is a balancing act due to the danger inherent to severe hypoxia.…”

“…Conditioning approaches can be applied to strengthen mitochondrial functions, increase the endogenous oxidative stress defense and reduce neuroinflammation [ 173 ], processes that are all central in HD pathogenesis (see below). Such strategies are able to improve brain tissue resilience and thus brain cell health, which has been suggested to be an important feature of future neurodegeneration treatment strategies with greater translational potential than previous strategies developed in pre-clinical models [ 174 ]. Furthermore, the relatively early average onset as compared to sporadic neurodegenerative diseases render HD an attractive target for conditioning approaches, particularly if conditioning is confirmed to be less efficient in older persons, as discussed in Section 3 .…”

Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?

“…In addition, identified mutations in the HTRA2 gene cause hereditary tremors in humans which can progress into Parkinson’s disease [ 168 , 169 , 170 ]. Furthermore, HtrA2 has been found to co-localize with α-synuclein within Lewy bodies, and it could be shown that HtrA2 can reduce the propensity of α-synuclein seeding while also aiding the removal of already aggregated α-synuclein [ 45 , 171 , 172 ]. In addition, the proteolytic activity of HtrA2 is affected by PINK1, another protein whose dysfunction is linked to Parkinson’s disease.…”

“…Another evolutionally conserved mitochondrial protease is the hexameric Lon protease, which plays an important role in clearing oxidatively damaged proteins in mitochondria and which has been found in high concentrations in the substantia nigra of patients with Parkinson’s disease. It has also demonstrated an ability to reduce the aggregation propensity of α-synuclein [ 45 ]. Specifically, inhibiting Lon protease with small molecule inhibitors led to an attenuation of α-synuclein aggregation in a cell culture model [ 45 , 176 ].…”

“…Despite the existence of functional clearance systems, such as the autophagy, proteasomal as well as lysosomal systems for cytoplasmic α-synuclein, the reason for the impaired clearance remains unknown, though alterations in post-translational modification patterns [ 39 , 40 , 41 ] might play a role in the observed relocalization from lysosomes to mitochondria upon chaperone inhibition [ 34 ]. This subcellular relocalization of α-synuclein might facilitate mitochondrial membrane disruption [ 42 , 43 , 44 ], indicating the possible likelihood of proteolytic processing of α-synuclein by mitochondrial proteases [ 5 , 34 , 35 , 45 ]. Herein, we will review the current knowledge on the role of molecular chaperones in the regulation of the physiological function as well as the direct consequences of impairing these interactions, which might mark crucial aspects of the initial stages of the structural transition of α-synuclein towards its pathological states.…”