Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1

Abstract

Aggregation of a-synuclein (aS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of aS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that aS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, aS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age-dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous aS. In contrast, siRNA-mediated downregulation of aS results in elongated mitochondria in cell culture. aS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, aS prevents fusion of differently labelled mitochondrial populations. Thus, aS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of aS is rescued by coexpression of PINK1, parkin or DJ-1 but not the PD-associated mutations PINK1 G309D and parkin D1-79 or by DJ-1 C106A.

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

“…A number of PD-related proteins, including SNCA, PINK1, PRKN, PARK7, and LRRK2, have been reported to regulate mitochondrial fission and fusion [42–46], suggesting that altered mitochondrial dynamics contributes to neurodegeneration. We found substantial changes in levels of mitochondrial fission and fusion proteins, with a consistent decrease of DNM1L in brain tissues from GBA-PD patients and Gba L444P/WT mice.…”

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

“…Inhibition of Pink1 induces fragmented mitochondria, altered cristae morphology and reduced membrane potential 34 . Overexpression of Pink1 rescues mitochondrial fragmentation 35 , increases mitochondrial interconnectivity 12 and reduces mitochondrial dysfunction and apoptosis as well 36 . Our present study for the first time reveals that Pink1 can maintain the cardiac structure and function through its protective effect on the mitochondria.…”

α-Synuclein Reduces Tension and Increases Undulations in Simulations of Small Unilamellar Vesicles

“…Collectively, these findings have led to the hypothesis that aSyn inhibits fusion through direct alteration of the lipid bilayer's physical properties (2,3,(5)(6)(7). Once biophysical mechanisms for these inhibitory effects are understood, the impact is expected to extend to other proteins with similar amphipathic characteristics.…”

“…For example, apolipoprotein A-I, a related, but larger membrane binding protein that shares aSyn's amphipathic 11-mer repeat sequence, was also shown to inhibit vesicle fusion. On the other hand, a short (but still amphipathic) segment of aSyn has no inhibitory effect (3). Exactly what bestows aSyn with its antifusogenic activity, be it sequence-specific or a more generic feature of all amphipathic helices, remains unknown.…”

“…In the case of gel-phase SUVs, thermodynamic measurements prompted the hypothesis that aSyn anneals defect zones in the lipid matrix, thus inhibiting SUV fusion by relieving curvature stress (3,7). However, no direct experimental measurements to test this hypothesis have yet been made.…”