Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control

Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure. © 20221

AMPK Regulates Circadian Rhythms in a Tissue- and Isoform-Specific Manner

AMP protein kinase (AMPK) plays an important role in food intake and energy metabolism, which are synchronized to the light-dark cycle. In vitro, AMPK affects the circadian rhythm by regulating at least two clock components, CKIα and CRY1, via direct phosphorylation. However, it is not known whether the catalytic activity of AMPK actually regulates circadian rhythm in vivo.THE CATALYTIC SUBUNIT OF AMPK HAS TWO ISOFORMS: α1 and α2. We investigate the circadian rhythm of behavior, physiology and gene expression in AMPKα1-/- and AMPKα2-/- mice. We found that both α1-/- and α2-/- mice are able to maintain a circadian rhythm of activity in dark-dark (DD) cycle, but α1-/- mice have a shorter circadian period whereas α2-/- mice showed a tendency toward a slightly longer circadian period. Furthermore, the circadian rhythm of body temperature was dampened in α1-/- mice, but not in α2-/- mice. The circadian pattern of core clock gene expression was severely disrupted in fat in α1-/- mice, but it was severely disrupted in the heart and skeletal muscle of α2-/- mice. Interestingly, other genes that showed circadian pattern of expression were dysreguated in both α1-/- and α2-/- mice. The circadian rhythm of nicotinamide phosphoryl-transferase (NAMPT) activity, which converts nicotinamide (NAM) to NAD+, is an important regulator of the circadian clock. We found that the NAMPT rhythm was absent in AMPK-deficient tissues and cells.This study demonstrates that the catalytic activity of AMPK regulates circadian rhythm of behavior, energy metabolism and gene expression in isoform- and tissue-specific manners

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice

The Natural Alkaloid Palmatine Selectively Induces Mitophagy and Restores Mitochondrial Function in an Alzheimer’s Disease Mouse Model

Palmatine, a natural alkaloid found in various plants, has been reported to have diverse pharmacological and biological effects, including anti-inflammatory, antioxidant, and cardiovascular effects. However, the role of palmatine in mitophagy, a fundamental process crucial for maintaining mitochondrial function, remains elusive. In this study, we found that palmatine efficiently induces mitophagy in various human cell lines. Palmatine specifically induces mitophagy and subsequently stimulates mitochondrial biogenesis. Palmatine did not interfere with mitochondrial function, similar to CCCP, suggesting that palmatine is not toxic to mitochondria. Importantly, palmatine treatment alleviated mitochondrial dysfunction in PINK1-knockout MEFs. Moreover, the administration of palmatine resulted in significant improvements in cognitive function and restored mitochondrial function in an Alzheimer’s disease mouse model. This study identifies palmatine as a novel inducer of selective mitophagy. Our results suggest that palmatine-mediated mitophagy induction could be a potential strategy for Alzheimer’s disease treatment and that natural alkaloids are potential sources of mitophagy inducers

PINK1 alleviates thermal hypersensitivity in a paclitaxel-induced Drosophila model of peripheral neuropathy

Paclitaxel is a representative anticancer drug that induces chemotherapy-induced peripheral neuropathy (CIPN), a common side effect that limits many anticancer chemotherapies. Although PINK1, a key mediator of mitochondrial quality control, has been shown to protect neuronal cells from various toxic treatments, the role of PINK1 in CIPN has not been investigated. Here, we examined the effect of PINK1 expression on CIPN using a recently established paclitaxel-induced peripheral neuropathy model in Drosophila larvae. We found that the class IV dendritic arborization (C4da) sensory neuron-specific expression of PINK1 significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype. In contrast, knockdown of PINK1 resulted in an increase in thermal hypersensitivity, suggesting a critical role for PINK1 in sensory neuron-mediated thermal nociceptive sensitivity. Interestingly, analysis of the C4da neuron morphology suggests that PINK1 expression alleviates paclitaxel-induced thermal hypersensitivity by means other than preventing alterations in sensory dendrites in C4da neurons. We found that paclitaxel induces mitochondrial dysfunction in C4da neurons and that PINK1 expression suppressed the paclitaxel-induced increase in mitophagy in C4da neurons. These results suggest that PINK1 mitigates paclitaxel-induced sensory dendrite alterations and restores mitochondrial homeostasis in C4da neurons and that improvement in mitochondrial quality control could be a promising strategy for the treatment of CIPN. © 2020 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.TRU

Relationship between antiapoptotic molecules and metastatic potency and the involvement of DNA-dependent protein kinase in the chemosensitization of metastatic human cancer cells by epidermal growth factor receptor blockade

The failure to treat metastatic cancer with multidrug resistance is a major problem for successful cancer therapy, and the molecular basis for the association of metastatic phenotype with resistance to therapy is still unclear. In this study, we revealed that various metastatic cancer cells showed consis-tently higher levels of antiapoptotic proteins, including Bcl-2, nuclear factor-B, MDM2, DNA-dependent protein kinase (DNA-PK), and epidermal growth factor receptor (EGFR), and lower levels of proapoptotic proteins, including Bax and p53 than low metastatic parental cells. This was followed by chemo- and radioresistance in metastatic cancer cells com-pared with their parental cells. EGFR and DNA-PK activity, which are known to be associated with chemo- and radioresis-tance, were demonstrated to be mutually regulated by eac