Mitochondrial Biogenesis: Cell-Cycle-Dependent Investment in Making Mitochondria

SummaryMitochondria cannot be made de novo, so pre-existing mitochondria must be inherited at each cell division. A new study demonstrates cell-cycle-dependent regulation of the activity of the TOM translocase complex to induce mitochondrial biogenesis during the M phase of the cell cycle

Review

Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. Mitochondria also serve as Ca2+ sinks and anabolic factories and are therefore essential for neuronal function and survival. Dysregulation of neuronal bioenergetics is increasingly implicated in neurodegenerative disorders, particularly Parkinson's disease. This review describes the role of mitochondria in energy metabolism under resting conditions and during synaptic transmission, and presents evidence for the contribution of neuronal mitochondrial dysfunction to Parkinson's disease

Infektionsrate von mittels Kirschner-Draht versorgten kindlichen distalen Radiusfrakturen. Perkutane Drahtlage vs. versenkte Kirschner-Drahtlage

In der Kindertraumatologie ist die distale Unterarmfraktur die häufigste Fraktur überhaupt: In 25% aller kindlichen Frakturen ist der Radius mit betroffen. Liegt die Dislokation außerhalb der spontanen Korrekturgrenzen, innerhalb derer sich Fehlstellungen im Rahmen des Wachstums noch korrigieren, besteht die Indikation zur operativen Behandlung. Die kindlichen distalen Unterarmfrakturen werden meist geschlossen reponiert und mittels K-Drähten, die durch die Haut eingebracht werden, stabilisiert. Häufig werden die Enden der Drähte gekürzt und die Haut darüber vollständig verschlossen um Infekte zu vermeiden. Allerdings gibt es auch die Technik der überstehenden Drahtenden, die ein einfacheres Entfernen der Drähte nach Konsolidierung der Fraktur in einer kurzen Lachgasanästhesie erlaubt. Der Aufwand für Familien und Klinik ist personell, organisatorisch und finanziell deutlich geringer, als die K-Drahtentfernung im Op unter Vollnarkose. Zudem entfällt das gesundheitliche Risiko der Narkose für das Kind. Im Krankenhaus der Barmherzigen Brüder Regensburg, Klinik St. Hedwig wird seit 5 Jahren die Technik der überstehenden Drahtenden praktiziert und es wurde kein Fall gesehen, der einen Infekt (weder oberflächlich noch tief) gezeigt hatte. Hierzu wurde eine retrospektive Studie am eigenen Klientel mit 157 distalen Radiusfrakturen, die mit überstehender K-Drähte behandelt wurden, durchgeführt. Wie erwartet zeigte sich kein Infekt durch die K-Drahtenden. Allerdings war in einer Patienten-Umfrage im Rahmen der Studie die Zufriedenheit der Familien mit dem Drahtzug in der Ambulanz geringer als erwartet. Hier müssen sprachliche, kulturelle und auch psychologische Gegebenheiten sicher noch mehr berücksichtigt werden

Kill one or kill the many: Interplay between mitophagy and apoptosis

Mitochondria are key players of cellular metabolism, Ca2+ homeostasis, and apoptosis. The functionality of mitochondria is tightly regulated, and dysfunctional mitochondria are removed via mitophagy, a specialized form of autophagy that is compromised in hereditary forms of Parkinson's disease. Through mitophagy, cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of proapoptotic BCL-2 family proteins located on the outer mitochondrial membrane. Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases (caspases). We are only beginning to understand how the choice between mitophagy and the activation of caspases is determined on the mitochondrial surface. Intriguingly in neurons, caspase activation also plays a non-apoptotic role in synaptic plasticity. Here we review the current knowledge on the interplay between mitophagy and caspase activation with a special focus on the central nervous system

Kill one or kill the many: interplay between mitophagy and apoptosis

Mitochondria are key players of cellular metabolism, Ca2+ homeostasis, and apoptosis. The functionality of mitochondria is tightly regulated, and dysfunctional mitochondria are removed via mitophagy, a specialized form of autophagy that is compromised in hereditary forms of Parkinson's disease. Through mitophagy, cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of proapoptotic BCL-2 family proteins located on the outer mitochondrial membrane. Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases (caspases). We are only beginning to understand how the choice between mitophagy and the activation of caspases is determined on the mitochondrial surface. Intriguingly in neurons, caspase activation also plays a non-apoptotic role in synaptic plasticity. Here we review the current knowledge on the interplay between mitophagy and caspase activation with a special focus on the central nervous system

Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons

Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction

Glucose-Induced Regulation of Protein Import Receptor Tom22 by Cytosolic and Mitochondria-Bound Kinases

SummaryMost mitochondrial proteins are imported by the translocase of the outer mitochondrial membrane (TOM). Tom22 functions as central receptor and transfers preproteins to the import pore. Casein kinase 2 (CK2) constitutively phosphorylates the cytosolic precursor of Tom22 at Ser44 and Ser46 and, thus, promotes its import. It is unknown whether Tom22 is regulated under different metabolic conditions. We report that CK1, which is involved in glucose-induced signal transduction, is bound to mitochondria. CK1 phosphorylates Tom22 at Thr57 and stimulates the assembly of Tom22 and Tom20. In contrast, protein kinase A (PKA), which is also activated by the addition of glucose, phosphorylates the precursor of Tom22 at Thr76 and impairs its import. Thus, PKA functions in an opposite manner to CK1 and CK2. Our results reveal that three kinases regulate the import and assembly of Tom22, demonstrating that the central receptor is a major target for the posttranslational regulation of mitochondrial protein import

Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment.

Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans-activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT-MTScs-FXN fusion protein to decrease neurodegeneration markers on frataxin-depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues. In mice models of the disease, we tested the ability of TAT-MTScs-FXN to penetrate the mitochondria and its effect on lifespan. In DRG neurons, treatment with TAT-MTScs-FXN increased cell survival, decreased neurite degeneration and reduced apoptotic markers, such as α-fodrin cleavage and caspase 9 activation. Also, we show that heat-shock protein 60 (HSP60), a molecular chaperone targeted to mitochondria, suffered an impaired processing in frataxin-deficient neurons that was relieved by TAT-MTScs-FXN addition. In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia. J Cell Mol Med 2018 Feb; 22(2):834-848