Selective autophagy in type 2 diabetes-associated cognitive dysfunction: Insightful mechanisms and therapies.

The IL-6 cytokine family activates intracellular signaling pathways through glycoprotein-130 (gp130), and this signaling has established regulatory roles in muscle glucose metabolism and proteostasis. Although the IL-6 family has been implicated as myokines regulating the muscles' metabolic response to exercise, gp130's role in mitochondrial quality control involving fission, fusion, mitophagy, and biogenesis is not well understood. Therefore, we examined gp130's role in basal and exercise-trained muscle mitochondrial quality control. Muscles from C57BL/6, skeletal muscle-specific gp130 knockout (KO) mice, and C2C12 myotubes, were examined. KO did not alter treadmill run-to-fatigue or indices of mitochondrial content [cytochrome- c oxidase (COX) activity] or biogenesis (AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, and COX IV). KO increased mitochondrial fission 1 protein (FIS-1) while suppressing mitofusin-1 (MFN-1), which was recapitulated in myotubes after gp130 knockdown. KO induced ubiquitin-binding protein p62, Parkin, and ubiquitin in isolated mitochondria from gastrocnemius muscles. Knockdown of gp130 in myotubes suppressed STAT3 and induced accumulation of microtubule-associated protein-1 light chain 3B (LC3)-II relative to LC3-I. Suppression of myotube STAT3 did not alter FIS-1 or MFN-1. Exercise training increased muscle gp130 and suppressed STAT3. KO did not alter the exercise-training induction of COX activity, biogenesis, FIS-1, or Beclin-1. KO increased MFN-1 and suppressed 4-hydroxynonenal after exercise training. These findings suggest a role for gp130 in the modulation of mitochondrial dynamics and autophagic processes. NEW & NOTEWORTHY Although the IL-6 family of cytokines has been implicated in the regulation of skeletal muscle protein turnover and metabolism, less is understood about its role in mitochondrial quality control. We examined the glycoprotein-130 receptor in the regulation of skeletal muscle mitochondria quality control in the basal and exercise-trained states. We report that the muscle glycoprotein-130 receptor modulates basal mitochondrial dynamics and autophagic processes and is not necessary for exercise-training mitochondrial adaptations to quality control.

Mitochondrial transfer between cell crosstalk - An emerging role in mitochondrial quality control.

The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect.

Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.

Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity. Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4‘,6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1

Mitophagy is the process of selective mitochondrial degradation via autophagy, which has an important role in mitochondrial quality control. Very little is known, however, about the molecular mechanism of mitophagy. A genome-wide yeast mutant screen for mitophagy-defective strains identified 32 mutants with a block in mitophagy, in addition to the known autophagy-related (ATG) gene mutants. We further characterized one of these mutants, ylr356wDelta that corresponds to a gene whose function has not been identified. YLR356W is a mitophagy-specific gene that was not required for other types of selective autophagy or macroautophagy. The deletion of YLR356W partially inhibited mitophagy during starvation, whereas there was an almost complete inhibition at post-log phase. Accordingly, we have named this gene ATG33. The new mutants identified in this analysis will provide a useful foundation for researchers interested in the study of mitochondrial homeostasis and quality control.

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

The mitochondrial quality control system is the principal regulatory framework governing mitochondrial quantity, morphology, distribution, and functional integrity. This surveillance and regulatory machinery is essential for preserving cellular homeostasis and determining cellular differentiation. Mitochondria play a central role in maintaining the dynamic equilibrium between osteogenic differentiation and osteoclastic differentiation. Dysregulation of mitochondrial quality control can lead to disrupted mitochondrial homeostasis and functional impairments, disrupting the physiological processes of bone formation and bone resorption. However, comprehensive reviews elucidating the relationship between mitochondrial quality control and bone homeostasis are conspicuously lacking. This review systematically deconstructs the molecular architecture of mitochondrial quality control, elucidating the regulatory mechanism of each part (mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondrial redox) in bone-related cells. In addition, the mitochondrial quality control system in orchestrating cellular physiological activities is summarized to establish its indispensable in governing cellular homeostatic networks. Furthermore, the regulatory roles of the mitochondrial quality control system in bone-related cells and the balance between bone formation and resorption are reviewed. Finally, this review delineates the dysregulation of mitochondrial quality control in bone metabolic diseases and further advances mitochondrial quality control-targeted approaches for restoring mitochondria homeostasis, offering transformative strategies to treat bone metabolic diseases.

Cardiotoxicity is the major side effect of anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin), though being the most commonly used chemotherapy drugs and the mainstay of therapy in solid and hematological neoplasms. Advances in the field of cardio-oncology have expanded our understanding of the molecular mechanisms underlying anthracycline-induced cardiotoxicity (AIC). AIC has a complex pathogenesis that includes a variety of aspects such as oxidative stress, autophagy, and inflammation. Emerging evidence has strongly suggested that the loss of mitochondrial quality control (MQC) plays an important role in the progression of AIC. Mitochondria are vital organelles in the cardiomyocytes that serve as the key regulators of reactive oxygen species (ROS) production, energy metabolism, cell death, and calcium buffering. However, as mitochondria are susceptible to damage, the MQC system, including mitochondrial dynamics (fusion/fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control, appears to be crucial in maintaining mitochondrial homeostasis. In this review, we summarize current evidence on the role of MQC in the pathogenesis of AIC and highlight the therapeutic potential of restoring the cardiomyocyte MQC system in the prevention and intervention of AIC.

Functional analysis of the selective autophagy related gene Acatg11 in Acremonium chrysogenum

Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control

Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury.

A healthy mitochondrial network produces a large amount of ATP and biosynthetic intermediates to provide sufficient energy for myocardium and maintain normal cell metabolism. Mitochondria form a dynamic and interconnected network involved in various cellular metabolic signaling pathways. As mitochondria are damaged, controlling mitochondrial quantity and quality is activated by changing their morphology and tube network structure, mitophagy, and biogenesis to replenish a healthy mitochondrial network to preserve cell function. There is no doubt that mitochondrial dysfunction has become a key factor in many diseases. Ischemia/reperfusion (IR) injury is a pathological manifestation of various heart diseases. Cardiac ischemia causes temporary tissue and organelle damage. Although reperfusion is essential to compensate for nutrient deficiency, blood flow restoration inconsequently further kills the previously ischemic cardiomyocytes. To date, dysfunctional mitochondria and disturbed mitochondrial quality control have been identified as critical IR injury mechanisms. Many researchers have detected abnormal mitochondrial morphology and mitophagy, as well as aberrant levels and activity of mitochondrial biogenesis factors in the IR injury model. Although mitochondrial damage is well-known in myocardial IR injury, the causal relationship between abnormal mitochondrial quality control and IR injury has not been established. This review briefly describes the molecular mechanisms of mitochondrial quality control, summarizes our current understanding of the complex role of mitochondrial quality control in IR injury, and finally speculates on the possibility of targeted control of mitochondria and the methods available to mitigate IR injury.

The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. However, when MALM is inhibited, Mieap induces vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulf and degrade the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impairs both MALM and MIV generation. These results suggest that Mieap plays a pivotal role in mitochondrial quality control by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect. Citation Format: Yasuyuki Nakamura, Hiroki Kamino, Hitoya Sano, Hirofumi Arakawa. Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-131. doi:10.1158/1538-7445.AM2013-LB-131

The maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4months in adult mouse skeletal muscle resulted in severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. Our data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health. Mitochondria play central roles in skeletal muscle physiology, including energy supply, regulation of energy-sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis. The maintenance of optimal mitochondrial content and function is therefore critical for muscle cells. Mitochondria are now well known as highly dynamic organelles, able to change their morphology through fusion and fission processes. Solid experimental evidence indicates that mitochondrial dynamics play key roles in mitochondrial quality control, and alteration in the expression of proteins regulating mitochondrial dynamics have been reported in many conditions associated with muscle atrophy and wasting. However, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. To address this issue, we investigated the impact of Drp1 (a protein regulating mitochondrial fission) knockdown, introduced via intramuscular injection of adeno-associated virus (AAV) on adult mouse skeletal muscle. Knocking down Drp1 for 4months resulted in very severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration and increases in markers of muscle regeneration, denervation, fibrosis, oxidative stress and impaired autophagy. Our findings indicate that Drp1 is essential for the maintenance of normal mitochondrial function and that Drp1 suppression severely impairs muscle health.