Mitochondrial Respiratory Dysfunction in Familiar Parkinsonism Associated with PINK1 Mutation

Piccoli, Cláudia; Sardanelli, Anna Maria; Scrima, Rosella; Ripoli, Maria; Quarato, Giovanni; D’Aprile, Annamaria; Bellomo, Francesco; Scacco, Salvatore; Michele, Giuseppe De; Filla, Alessandro; Iuso, Arcangela; Boffoli, Domenico; Capitanio, Nazzareno; Papa, Sergio

doi:10.1007/s11064-008-9729-2

Cited by 99 publications

(71 citation statements)

References 34 publications

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“…In agreement with other studies (Gandhi et al, 2009;Piccoli et al, 2008;Wood-Kaczmar et al, 2008), we did not observe differences in maximal activity for the OXPHOS complexes in PINK1-KD or PINK1-KO cells. However, we cannot exclude the possibility that the OXPHOS system might operate less efficiently in resting PINK1-deficient cells, thus explaining the depolarized .…”

Section: Discussionsupporting

confidence: 93%

Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance

Heeman

Haute

Aelvoet

et al. 2011

Journal of Cell Science

169

132

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SummaryLoss-of-function mutations in the gene encoding the mitochondrial PTEN-induced putative kinase 1 (PINK1) are a major cause of early-onset familial Parkinson's disease (PD). Recent studies have highlighted an important function for PINK1 in clearing depolarized mitochondria by mitophagy. However, the role of PINK1 in mitochondrial and cellular functioning in physiological conditions is still incompletely understood. Here, we investigate mitochondrial and cellular calcium (Ca 2+ ) homeostasis in PINK1-knockdown and PINK1-knockout mouse cells, both in basal metabolic conditions and after physiological stimulation, using unbiased automated live single-cell imaging in combination with organelle-specific fluorescent probes. Our data reveal that depletion of PINK1 induces moderate fragmentation of the mitochondrial network, mitochondrial membrane depolarization and increased production of reactive oxygen species. This results in reduced uptake of Ca 2+ by mitochondria after physiological stimulation. As a consequence, cells with knockdown or knockout of PINK1 display impaired mitochondrial ATP synthesis, which is exacerbated under conditions of increased ATP demand, thereby affecting cytosolic Ca 2+ extrusion. The impairment in energy maintenance was confirmed in the brain of PINK1-knockout mice by in vivo bioluminescence imaging. Our findings demonstrate a key role for PINK1 in the regulation of mitochondrial homeostasis and energy metabolism under physiological conditions.

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Section: Discussionsupporting

confidence: 93%

Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance

Heeman

Haute

Aelvoet

et al. 2011

Journal of Cell Science

169

132

View full text Add to dashboard Cite

show abstract

“…Piccoli and colleagues [262]also performed studies on fibroblasts from a patient with a PINK1 mutation and observed a low mitochondrial respiratory activity and increased oxygen radical production due to complex I inhibition, demonstrating clinically what has been shown experimentally.…”

Section: Ptenǧinduced Putative Kinase 1 (Pink1)mentioning

confidence: 69%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

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“…Consistent with these findings in Drosophila, patients with PINK1 or PARKIN mutations have indistinguishable clinical features and also show mitochondrial defects (1,15). Recent studies also suggest that Pink1 and Parkin regulate mitochondrial functions in mammals (16)(17)(18)(19). These findings underscore the central importance of the Pink1/Parkin pathway in regulating mitochondrial integrity and function.…”

Section: Central Role Of Mitochondrial Function In Pd Pathogenesismentioning

confidence: 72%

Protein degradation in Parkinson disease revisited: it’s complex

Guo²

2009

J. Clin. Invest.

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Parkinson disease (PD) is the second most common neurodegenerative disorder, and mutations in the genes PTEN-induced putative kinase 1 (PINK1, also known as Parkinson disease 6 [PARK6]), PARKIN (also known as PARK2), and DJ-1 (also known as PARK7) cause autosomal recessive forms of PD/parkinsonism. PINK1 encodes a protein with a mitochondrial targeting sequence and a putative serine/threonine kinase domain, and PINK1 is predominantly localized to mitochondria (1). The Parkin protein contains two RING finger motifs, has E3 ubiquitin ligase activity in vitro, and is largely localized to the cytosol (1). The endogenous DJ-1 protein is found in mitochondria and cytosol, but the function of DJ-1 is not entirely clear (1). Studies on the functions of these genes may provide important insights into PD pathogenesis. Prior studies on protein degradationMost PD patients have intraneuronal inclusions in the form of ubiquitin-positive Lewy bodies and Lewy neurites. Given the presence of Parkin in Lewy bodies and the putative role of Parkin as an E3 ligase, much of the initial work on Parkin was focused on its potential role in regulating protein degradation via the ubiquitin-proteasome system (UPS). Ubiquitination is accomplished by covalently linking the ubiquitin polypeptide (Ub) to a lysine residue in a specific protein substrate and requires the sequential action of an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase (2). E3 ubiquitin ligases can mediate monoubiquitination (the addition of a single Ub to the substrate protein), multiubiquitination (the addition of multiple single Ubs to different lysine residues in a target protein), and polyubiquitination (in which chains of four or more Ubs are formed by the linkage of Ub molecules to lysine residues in other Ub molecules) (2). These linkages are most often to lysine 48 (K48) or lysine 63 (K63) of the Ub polypeptide. Proteins to be degraded by the proteasome are largely K48 polyubiquitinated. In contrast, K63 polyubiquitination, as well as monoubiquitination and multiubiquitination, primarily function in non-degradative processes including signal transduction, transcriptional regulation, protein localization, and membrane trafficking (2).Previous studies suggested that Parkin could function as an E3 ligase for proteasome-mediated protein degradation (3). A handful of substrates of Parkin, including Parkin itself and an a-synuclein-interacting protein (Synphilin-1) (4), have been identified in vitro. If Parkin were indeed important in the degradative pathway in vivo, one would expect that the levels of its substrates should increase in Parkinknockout mice. Unexpectedly, however, most of the substrates studied, including Synphilin-1, did not accumulate in Parkinnull mice (5). In addition, several studies have revealed that Parkin preferentially catalyzes monoubiquitination and K63-linked polyubiquitination of substrates including Synphilin-1 (6-8). These latter observations may offer potential explanations for the lack of substrate accumulation in vivo b...

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Mitochondrial Respiratory Dysfunction in Familiar Parkinsonism Associated with PINK1 Mutation

Cited by 99 publications

References 34 publications

Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance

Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Protein degradation in Parkinson disease revisited: it’s complex

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