Mitochondrial Quality Control Pathways Research Articles

P.5.c.002 - Mitochondria-targeted antioxidant SkQ1 reduces the death of dopaminergic neurons in the model of Parkinson’s disease in mice

Mitochondria, the powerhouse of the neural cells in the brain, are also the seat of certain essential gene signaling pathways that control neuronal functions. Deterioration of mitochondrial functions has been widely reported in normal aging as well as in a spectrum of age-associated neurological diseases, including Parkinson’s disease (PD). Evidences accumulated in the recent past provide not only advanced information on the causes of mitochondrial bioenergetics defects and redox imbalance in PD brains, but also much insight into mitochondrial biogenesis, quality control of mitochondrial proteins, and genes, which regulate intra- and extra-mitochondrial signaling that control the general health of neural cells. The mitochondrial quality control machinery is affected in aging and especially in PD, thus affecting intraneuronal protein transport and degradation, which are primarily responsible for accumulation of misfolded proteins and mitochondrial damage in sporadic as well as familial PD. Essentially we considered in the first half of this review, mitochondria-based targets such as mitochondrial oxidative stress and mitochondrial quality control pathways in PD, relevance of mitochondrial DNA mutations, mitophagy, mitochondrial proteases, mitochondrial flux, and finally mitochondria-based therapies possible for PD. Therapeutic aspects are considered in the later half and mitochondria-targeted antioxidant therapy, mitophagy enhancers, mitochondrial biogenesis boasters, mitochondrial dynamics modulators, and gene-based therapeutic approaches are discussed. The present review is a critical assessment of this information to distinguish some exemplary mitochondrial therapeutic targets, and provides a utilitarian perception of some avenues for therapeutic designs on identified mitochondrial targets for PD, a very incapacitating disorder of the geriatric population, world over.

Nonsyndromic Parkinson disease in a family with autosomal dominant optic atrophy due to OPA1 mutations.

Many genes implicated in familial Parkinson disease (PD) code for proteins with mitochondrial function.1 Several of these genes, including PINK1 and PARK2, are involved in mitophagy, a mitochondrial quality control pathway.2 We describe a family with 3 members affected by autosomal dominant optic atrophy in which 2 affected members also developed PD.

Moshi Song: An International Ballad.

Though Moshi Song is a relatively new face in the Wu laboratory at Stanford University in California, this postdoctoral fellow brings with her a world of experience. She graduated from the Beijing Forestry University with a BS degree in Biology before completing a 2-year MMS in Biomedicine at the Karolinska Institute in Stockholm, Sweden. Most recently, she completed her PhD in Molecular Cell Biology in the Dorn laboratory at Washington University in St Louis, where she was awarded the Spencer T. and Ann W. Olin Medical Science Fellow by the Division of Biology and Biomedical Sciences. When I was a very little kid, I wanted to be a school teacher. Both of my parents were teachers, although they didn’t want me to follow in their path. Ultimately, I decided to study biology when filling out the form of intention for my college entrance examination because I thought it would give me the opportunity to be involved in solving human puzzles as a life scientist. I realized I wanted to study abroad not long after starting college, and I took the GRE general test during my sophomore year. I received a great offer from the Karolinska Institute, where I did both coursework and benchwork. I also got to travel around Europe in more than 15 countries, seeing historic places and meeting people of various backgrounds. Stockholm is still my favorite city, but at the time I was young and did not want to stay in the same place for more than a few years. I applied to ten graduate programs in the United States to pursue my PhD …

Mitochondrial quality control pathways: PINK1 acts as a gatekeeper

Mitochondria have a pivotal role in the maintenance of cell homeostasis and survival. Mitochondria are involved in processes such as ATP production, reactive oxygen species production, apoptosis induction, calcium homeostasis and protein degradation. Thus, mechanisms that regulate the intrinsic quality of mitochondria have a crucial role in dictating overall cell fate. The importance of these well-regulated mechanisms is highlighted in disease scenarios such as neurodegeneration, cancer and neuromuscular atrophy. How mitochondria senses and regulates their intrinsic quality control, and consequently cell survival, is still not fully understood. In this review, we discuss the pathways that are at present considered as state-of-the-art for mitochondria quality control regulation, and highlight a mitochondrial protein–PINK1–that has revealed to act as a mitochondrial gatekeeper able to sense the presence of healthy or damaged mitochondria.

P 138 - A correlation between redox imbalance and altered mitochondrial quality control pathway in Autistic Spectrum Disorder

The Autistic Spectrum Disorder (ASD) refers to a range of conditions classified as neurodevelopmental disorders characteristic of the early childhood. Over the last 50 years, considerable efforts have been made to understand pathogenesis of ASD: it is generally accepted that a lot of causes could trigger the disease. Since growing evidences described an association between oxidative stress and mitochondrial dysfunction in ASD, we investigated the possible defects of mitochondrial quality control pathway as contributing factors to the altered redox homeostasis. Using freshly skin fibroblasts isolated from ASD patients and healthy subjects, we demonstrated in autistic cells an increased levels of 4HNE protein adducts - a major secondary product of lipid peroxidation - and catalase, one of the main enzymes of the cellular defensive system. Transmission electron microscope (TEM) analysis demonstrated an altered mitochondrial morphology in autistic fibroblasts. An increased expression of the genes that encode for molecules involved in mitochondrial fission/fusion processes, was also detected. In addition, overregulation of PINK1, but decreased Parkin expression, both associated to mitophagy process, were observed. Taken together our findings provide new insights on the possible contribution of the altered mitochondrial quality control pathway in the redox imbalance of ASD patients.

Discovery of Mieap‐regulated mitochondrial quality control as a new function of tumor suppressor p53

The tumor suppressor p53 gene is frequently mutated in human cancers, and the p53 protein suppresses cancer. However, the mechanism behind the p53‐mediated tumor suppression is still unclear. Recently, the mitochondria‐eating protein (Mieap) was identified as a p53‐inducible protein. Mieap induces the accumulation of lysosomal proteins within mitochondria (Mieap‐induced accumulation of lysosome‐like organelles within mitochondria, or MALM) in response to mitochondrial damage, and eliminates the oxidized mitochondrial proteins to repair unhealthy mitochondria. Furthermore, Mieap also induces vacuole‐like structures (Mieap‐induced vacuole, or MIV) to eat and degrade unhealthy mitochondria. Therefore, Mieap controls mitochondrial quality by repairing or eliminating unhealthy mitochondria by MALM or MIV, respectively. This mechanism is not mediated by canonical autophagy. Mieap‐deficient ApcMin/+ mice show strikingly high rates of intestinal tumor development as well as advanced‐grade adenomas and adenocarcinomas. The p53/Mieap/BCL2 interacting protein 3 mitochondrial quality control pathway is frequently inactivated in human colorectal cancers. Defects in Mieap‐regulated mitochondrial quality control lead to accumulation of unhealthy mitochondria in cancer cells. Cancer‐specific unhealthy mitochondria could contribute to cancer development and aggressiveness through mitochondrial reactive oxygen species and altered metabolism. Mieap‐regulated mitochondrial quality control is a newly discovered function of p53 that plays a critical role in tumor suppression.

Loss of laforin or malin results in increased Drp1 level and concomitant mitochondrial fragmentation in Lafora disease mouse models

Lafora disease (LD) is an autosomal recessive form of a fatal disorder characterized by the myoclonus epilepsy, ataxia, psychosis, dementia, and dysarthria. A hallmark of LD is the presence of abnormal glycogen inclusions called Lafora bodies in the affected tissues including the neurons. LD can be caused by defects either in the laforin phosphatase coded by the EPM2A gene or in the malin E3 ubiquitin ligase coded by the NHLRC1 gene. The mouse models of LD, created by the targeted disruption of the LD genes, display several neurodegenerative changes. Prominent among them are the autophagic defects, abnormally large lysosomes, neurofibrillary tangles, amyloid beta deposits, and abnormal mitochondria. However, whether or not such neurodegenerative changes are a direct effect of the loss of laforin/malin was not unequivocally established. Here, we show that laforin- or malin-deficient neurons and fibroblasts display a significantly higher number of fragmented mitochondria. Loss of laforin or malin resulted in increased levels of the mitochondrial fission GTPase Drp1, its enhanced mitochondrial targeting, and increased intracellular calcium levels. Intriguingly, laforin and malin display opposite effects on the cellular level of parkin, an ubiquitin ligase of Drp1; loss of laforin led to reduced levels of parkin while the loss of malin resulted in increased parkin levels. Laforin and malin, however, interact with and positively regulate the activity of parkin, thus explaining the molecular basis of increased Drp1 levels in LD tissues. Our results suggest that laforin and malin are novel regulators of mitochondrial quality control pathway and that the mitochondrial dysfunction resulting from the increased Drp1 levels could underlie neuropathology in LD.

Beyond Deubiquitylation: USP30-Mediated Regulation of Mitochondrial Homeostasis.

Mutations or sequence aberrations in the Parkin gene are among the most common causes of autosomal recessive Parkinson's disorder (PD). Parkin, a cytoplasmic E3 ubiquitin ligase, is involved in mitochondrial quality control pathways, including mitochondrial fission and mitophagy by autophagy-related genes. Parkin mediates the covalent addition of ubiquitin (Ub) chains to Lys 6, Lys 11, and Lys 63 on diverse mitochondrial-related target proteins. USP30, a mitochondrial deubiquitinase, promotes mitochondrial fusion by mediating the deubiquitination of ubiquitylated forms of mitofusins, such as Mfn1 and Mfn2. USP30 preferentially mediates the removal of Ub chains from Lys 6 and Lys 11 on mitochondria-derived proteins. USP30 mediates the removal of the ubiquitin chains added by Parkin. It was demonstrated that overexpression of USP30 triggers the mitochondrial dynamic signaling toward elevated fusion and reduced fission and halts mitochondrial clearance via mitophagy. Although mounting lines of evidences reveal the pivotal role of Parkin in mitochondrial quality control pathways, the crucial role of deubiquitinases including the USP30 deubiquitinase is emerging. Herein, we review briefly the role of USP30 in the dynamic networks of mitochondrial quality control and its physiological implications.

PINK1 in the limelight: multiple functions of an eclectic protein in human health and disease.

The gene PINK1 [phosphatase and tensin homologue (PTEN)-induced putative kinase 1] encodes a serine/threonine kinase which was initially linked to the pathogenesis of a familial form of Parkinson's disease. Research on PINK1 has recently unravelled that its multiple functions extend well beyond neuroprotection, implicating this eclectic protein in a growing number of human pathologies, including cancer, diabetes, cardiopulmonary dysfunctions, and inflammation. Extensive studies have identified PINK1 as a crucial player in the mitochondrial quality control pathway, required to label damaged mitochondria and promote their elimination through an autophagic process (mitophagy). Mounting evidence now indicates that PINK1 activities are not restricted solely to mitophagy, and that different subcellular and even sub-mitochondrial pools of PINK1 are involved in distinct signalling cascades to regulate cell metabolism and survival. In this review, we provide a concise overview on the different functions of PINK1 and their potential role in human diseases. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Altered mitochondrial quality control signaling in muscle of old gastric cancer patients with cachexia

Mitochondrial dysfunction is involved in the loss of muscle featuring both aging and cancer cachexia (CC). Whether mitochondrial quality control (MQC) is altered in skeletal myocytes of old patients with CC is unclear. The present investigation therefore sought to preliminarily characterize MQC pathways in muscle of old gastric cancer patients with cachexia. The study followed a case-control cross-sectional design. Intraoperative biopsies of the rectus abdominis muscle were obtained from 18 patients with gastric adenocarcinoma (nine with CC and nine non-cachectic) and nine controls, and assayed for the expression of a set of MQC mediators. The mitofusin 2 expression was reduced in cancer patients compared with controls, independent of CC. Fission protein 1 was instead up-regulated in CC patients relative to the other groups. The mitophagy regulators PTEN-induced putative kinase 1 and Parkin were both down-regulated in cancer patients compared with controls. The ratio between the protein content of the lipidated and non-lipidated forms of microtubule-associated protein 1 light chain 3B was lower in CC patients relative to controls and non-cachectic cancer patients. Finally, the expression of autophagy-associated protein 7, lysosome-associated membrane protein 2, peroxisome proliferator-activated receptor-γ coactivator-1α, and mitochondrial transcription factor A was unvarying among groups. Collectively, our findings indicate that, in old patients with gastric cancer, cachexia is associated with derangements of the muscular MQC axis at several checkpoints: mitochondrial dynamics, mitochondrial tagging for disposal, and mitophagy signaling. Further investigations are needed to corroborate these preliminary findings and determine whether MQC pathways may become target for future interventions.

Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway.

Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2-deficient mice revealed that aging-induced Mfn2 decrease underlies the age-related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age-related mitochondrial dysfunction. Interestingly, aging-induced Mfn2 deficiency triggers a ROS-dependent adaptive signaling pathway through induction of HIF1α transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.

The mitochondrial kinase PINK1: functions beyond mitophagy.

Mutations in the genes encoding the mitochondrial kinase PINK1 and the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson's disease (PD). Pioneering work in Drosophila melanogaster revealed that the loss of PINK1 or Parkin function causes similar phenotypes including dysfunctional mitochondria. Further research showed that PINK1 can act upstream of Parkin in a mitochondrial quality control pathway to induce removal of damaged mitochondria in a process called mitophagy. Albeit the PINK1/Parkin-induced mitophagy pathway is well established and has recently been elucidated in great detail, its pathophysiological relevance is being debated. Mounting evidence indicates that PINK1 has additional functions, for example, in regulating complex I activity and maintaining neuronal viability in response to stress. Here, we discuss mitophagy-dependent and -independent functions of PINK1 and their possible role in PD pathogenesis. Mutations in the PINK1 gene, encoding a mitochondrial kinase, are associated with autosomal recessive Parkinson's disease. In this review, we summarize and discuss the functional roles of PINK1 in maintaining mitochondrial integrity, eliminating damaged mitochondria, and promoting cell survival. This article is part of a special issue on Parkinson disease.

Mitochondrial Quality Control and Muscle Mass Maintenance.

Loss of muscle mass and force occurs in many diseases such as disuse/inactivity, diabetes, cancer, renal, and cardiac failure and in aging-sarcopenia. In these catabolic conditions the mitochondrial content, morphology and function are greatly affected. The changes of mitochondrial network influence the production of reactive oxygen species (ROS) that play an important role in muscle function. Moreover, dysfunctional mitochondria trigger catabolic signaling pathways which feed-forward to the nucleus to promote the activation of muscle atrophy. Exercise, on the other hand, improves mitochondrial function by activating mitochondrial biogenesis and mitophagy, possibly playing an important part in the beneficial effects of physical activity in several diseases. Optimized mitochondrial function is strictly maintained by the coordinated activation of different mitochondrial quality control pathways. In this review we outline the current knowledge linking mitochondria-dependent signaling pathways to muscle homeostasis in aging and disease and the resulting implications for the development of novel therapeutic approaches to prevent muscle loss.

A Ubl/ubiquitin switch in the activation of Parkin.

Mutations in Parkin and PINK1 cause an inherited early-onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK1 kinase activity releases the auto-inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho-ubiquitin (pUb) and the ubiquitin-like domain (Ubl) of Parkin as a key element. By mutagenesis and SAXS, we show that pUb binds to RING1 of Parkin at a site formed by His302 and Arg305. pUb binding promotes disengagement of the Ubl from RING1 and subsequent Parkin phosphorylation. A crystal structure of Parkin Δ86–130 at 2.54 Å resolution allowed the design of mutations that specifically release the Ubl domain from RING1. These mutations mimic pUb binding and promote Parkin phosphorylation. Measurements of the E2 ubiquitin-conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pUb binding.

Abstract LB-067: Critical role of Mieap, a p53-inducible protein, in intestinal tumor suppression

Abstract Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1,2). Two mitochondrial outer membrane proteins, BNIP3 and NIX are essential mediators of MALM (3). 14-3-3gamma mediates the degradation of oxidized mitochondrial proteins in the MALM function (4). The Mieap-regulated mitochondrial quality control pathway was inactivated in almost 80% of colorectal cancer patients (5). Here, we report that Mieap plays a critical role in mouse intestinal tumor suppression. To investigate a role of Mieap in intestinal tumorigenesis, we generated the Mieap-deficient ApcMIN/+ mice. The ApcMIN/+ mice with the Mieap+/− and Mieap−/− genetic background revealed the remarkable shortening of the lifetime, compared to ApcMIN/+ mice. Mieap deficiency caused the increased number and size of the intestinal tumors in ApcMIN/+ mice. In addition, the tumors in the Mieap-deficient ApcMIN/+ mice showed more advanced grade of malignancy and often became cancerous. The mitochondria in the intestine and tumor of the Mieap-deficient ApcMIN/+ mice were morphologically unhealthy and generated high level of reactive oxygen species. These results suggest that Mieap plays a critical role in intestinal tumor suppression through mitochondrial quality control and prevention of mitochondrial oxidative stress. The Mieap-regulated mitochondrial quality control is a critical function for p53 tumor suppressor. (1) Miyamoto Y, Kitamura N, Nakamura Y, Futamura M, Miyamoto T, Yoshida M, Ono M, Ichinose S, Arakawa H. Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control. PLoS ONE 6: e16054, 2011. This paper was highly evaluated by F1000 (Must Read, Rating 8; Evaluated by Rial E: 2011. F1000.com/8253956) (2) Kitamura N, Nakamura Y, Miyamoto Y, Miyamoto T, Kabu K, Yoshida M, Futamura M, Ichinose S, Arakawa H. Mieap, a p53-indicuble protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. PLoS ONE 6: e16060, 2011. (3) Nakamura Y, Kitamura N, Shinogi D, Yoshida M, Goda O, Murai R, Kamino H, Arakawa H. BNIP3 and NIX mediate Mieap-induced accumulation of lysosomal proteins within mitochondria. PLoS ONE 7: e30767, 2012. (4) Miyamoto T, Kitamura N, Ono M, Nakamura Y, Yoshida M, Kamino H, Murai R, Yamada T, Arakawa H. Identification of 14-3-3γ as a Mieap-interacting protein and its role in mitochondrial quality control. Scientific Reports 2: 379, 2012. (5) Kamino H, Nakamura Y, Kitamura N, Futamura M, Yoshida M, Murai R, Saito Y, Sano H, Kanai Y, Moriya Y, Arakawa H. Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal cancer. AACR annual meeting 2013 (Washington D.C.): abstract number 1687 Citation Format: Yasuyuki Nakamura, Masayuki Tsuneki, Takashi Kinjyo, Noriaki Kitamura, Hirofumi Arakawa. Critical role of Mieap, a p53-inducible protein, in intestinal tumor suppression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-067. doi:10.1158/1538-7445.AM2015-LB-067

Mitochondrial quality control pathways as determinants of metabolic health.

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy – termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging.

Activation of the E3 ubiquitin ligase Parkin.

The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266-278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025-1026]. Recently resolved partial crystal structures of Parkin showed a 'closed', auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099-2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451-1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of 'opening' conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488-3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure-function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.

Parkin structure and function.

Mutations in the parkin or PINK1 genes are the leading cause of the autosomal recessive form of Parkinson’s disease. The gene products, the E3 ubiquitin ligase parkin and the serine/threonine kinase PINK1, are neuroprotective proteins, which act together in a mitochondrial quality control pathway. Here, we review the structure of parkin and mechanisms of its autoinhibition and function as a ubiquitin ligase. We present a model for the recruitment and activation of parkin as a key regulatory step in the clearance of depolarized or damaged mitochondria by autophagy (mitophagy). We conclude with a brief overview of other functions of parkin and considerations for drug discovery in the mitochondrial quality control pathway.

A polyubiquitin chain reaction: parkin recruitment to damaged mitochondria.

Mutations in the E3 ubiquitin ligase Parkin or the mitochondrial kinase PINK1 cause autosomal recessive forms of Parkinson’s disease [1, 2]. Genetic and cell biological studies have implicated PINK1 and Parkin as critical elements in mitophagy, a mitochondrial quality control pathway that involves the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system [1, 2]. Under basal conditions, PINK1 is processed by mitochondrial proteases and targeted for degradation by the UPS [1, 2]. Following persistent mitochondrial damage (e.g., treatment with the mitochondrial uncoupling agent CCCP) PINK1 is stabilized and accumulates in an active form on the outer mitochondrial membrane [1, 2]. Although PINK1 activity is essential for the mitochondrial recruitment of cytoplasmic Parkin and for the subsequent ubiquitin-dependent clearance of damaged mitochondria, the mode of Parkin activation and recruitment has been elusive [1, 2].

Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan.

Aging of biological systems is accompanied by degeneration of mitochondrial functions. Different pathways are active to counteract the processes which lead to mitochondrial dysfunction. Mitochondrial dynamics, the fission and fusion of mitochondria, is one of these quality control pathways. Mitophagy, the controlled degradation of mitochondria, is another one. Here we show that these pathways are linked. A double deletion mutant of Saccharomyces cerevisiae in which two essential components of the fission and fusion machinery, Dnm1 and Mgm1, are simultaneously ablated, contain wild-type like filamentous mitochondria, but are characterized by impaired respiration, an increased sensitivity to different stressors, increased mitochondrial protein carbonylation, and a decrease in mitophagy and replicative lifespan. These data show that a balanced mitochondrial dynamics and not a filamentous mitochondrial morphotype per se is the key for a long lifespan and demonstrate a cross-talk between two different mitochondrial quality control pathways.