bims-tofagi 2023-09-03 papers

on Mitophagy

Issue of 2023–09–03
eight papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
NBR1-mediated selective chloroplast autophagy is important to plant stress tolerance.
Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.
Mitophagy-promoting agents and their ability to promote healthy-aging.
Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review.
Mitophagy: from the dark into the spotlight.
Impaired mitophagy induces antimicrobial responses in macrophages infected with Mycobacterium tuberculosis.
Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.

Cell. 2023 Aug 21. pii: S0092-8674(23)00862-0. [Epub ahead of print]

PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.

Ruoxi Wang, Tina M Fortier, Fei Chai, Guangyan Miao, James L Shen, Lucas J Restrepo, Jeromy J DiGiacomo, Panagiotis D Velentzas, Eric H Baehrecke.

  Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.

Keywords:  Drosophila; ER-phagy; Keap1; PINK1; Parkin; Rtnl1

DOI:  https://doi.org/10.1016/j.cell.2023.08.008
Autophagy. 2023 Aug 27. 1-2

NBR1-mediated selective chloroplast autophagy is important to plant stress tolerance.

Hui Zhang, Qihua Ling.

  Macroautophagy/autophagy is a conserved process in eukaryotes responsible for degrading unwanted or damaged macromolecules and organelles through the lysosome or vacuole for recycling and reutilization. Our previous studies revealed the degradation of chloroplast proteins through a pathway dependent on the ubiquitin proteasome system, known as CHLORAD. Recently, we demonstrated a role for selective autophagy in regulating chloroplast protein import and enhancing stress tolerance in plants. Specifically, we found that K63-ubiquitination of TOC components at the chloroplast outer envelope membrane is recognized by the selective autophagy adaptor NBR1, leading to the degradation of TOC proteins under UV-B irradiation and heat stresses in Arabidopsis. This process was shown to control chloroplast protein import and influence photosynthetic activity. Based on our results, we have, for the first time, demonstrated that selective autophagy plays a vital role in chloroplast protein degradation, specifically in response to certain abiotic stresses.

Keywords:  Arabidopsis thaliana; NBR1; chloroplast; protein import; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2023.2251324
Commun Biol. 2023 08 29. 6(1): 889

Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.

Lianjiu Su, Jiahao Zhang, Jing Wang, Xiaozhan Wang, Edward Cao, Chen Yang, Qihao Sun, Ramadoss Sivakumar, Zhiyong Peng.

Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.

DOI: https://doi.org/10.1038/s42003-023-05226-x
Biochem Soc Trans. 2023 Aug 31. pii: BST20221363. [Epub ahead of print]

Mitophagy-promoting agents and their ability to promote healthy-aging.

Vijigisha Srivastava, Einav Gross.

  The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.

Keywords:  aging; lifespan; mitochondria; mitochondrial autophagy; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.1042/BST20221363
Cureus. 2023 Jul;15(7): e42550

Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review.

Breanne Kothe, Sarah Klein, Stephanie N Petrosky.

  The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action. The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patients at risk for these comorbidities.

Keywords:  age-related disease; aging; cholangiocarcinoma; colorectal cancer; neoplastic disease; neurodegenerative disease; osteoporosis; photo-aging; sarcopenia; urolithin a

DOI:  https://doi.org/10.7759/cureus.42550
Mol Plant. 2023 Aug 31. pii: S1674-2052(23)00250-2. [Epub ahead of print]

Mitophagy: from the dark into the spotlight.

Vivian Schmitt, Olivier Van Aken.

Despite the generally placid appearance of plants, many dynamic processes take place inside a plant cell. One such process that has garnered attention in recent years is termed 'autophagy'. While originally discovered in yeast, our understanding of autophagy in plants has improved significantly. Autophagy is considered a cellular recycling system in which cellular components or even entire organelles can be encapsulated by a membrane structure (autophagosome) and then transported to the vacuole (in plants) for degradation and re-use. One example of components degraded by autophagy are the mitochondria ('mitophagy'). Only a few years ago there was almost no information about plant mitophagy available, but lately several important studies have been published. A recent study identified an ATG8-FLZ-SnRK1 regulatory axis that connects carbon starvation signaling to mitophagy. In this Spotlight article, we focus on the function of mitochondrial FLZ proteins and SnRK1, and discuss them in context of current knowledge on the regulation of mitophagy in plants.

DOI: https://doi.org/10.1016/j.molp.2023.08.015
Cell Biosci. 2023 Aug 30. 13(1): 158

Impaired mitophagy induces antimicrobial responses in macrophages infected with Mycobacterium tuberculosis.

Junghwan Lee, Seong-Ahn Lee, Sang-Hun Son, Ji-Ae Choi, Tam Doan Nguyen, Jaewhan Kim, Doyi Son, Chang-Hwa Song.

   BACKGROUND: Mitophagy, mitochondrial selective autophagy, plays a pivotal role in the maintenance of cellular homeostasis in response to cellular stress. However, the role of mitophagy in macrophages during infection has not been elucidated. To determine whether mitophagy regulates intracellular pathogen survival, macrophages were infected with Mycobacterium tuberculosis (Mtb), an intracellular bacterium.
RESULTS: We showed that Mtb-infected macrophages induced mitophagy through BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) activation. In contrast, BNIP3-deficient macrophages failed to induce mitophagy, resulting in reduced mitochondrial membrane potential in response to Mtb infection. Moreover, the accumulation of damaged mitochondria due to BNIP3 deficiency generated higher levels of mitochondrial reactive oxygen species (mROS) compared to the control, suppressing the intracellular survival of Mtb. We observed that siBNIP3 suppressed intracellular Mtb in mice lungs.
CONCLUSION: We found that BNIP3 plays a critical role in the regulation of mitophagy during Mtb infection. The inhibition of mitophagy suppresses Mtb growth in macrophages through increased mROS production. Therefore, BNIP3 might be a novel therapeutic target for tuberculosis treatment.

Keywords:  BNIP3; Macrophage; Mitophagy; Mycobacterium tuberculosis; mROS

DOI:  https://doi.org/10.1186/s13578-023-01107-2
Exp Mol Med. 2023 Sep 01.

Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.

Soo-Jin Oh, Kihyoun Park, Seong Keun Sonn, Goo Taeg Oh, Myung-Shik Lee.

Mitophagy is an excellent example of selective autophagy that eliminates damaged or dysfunctional mitochondria, and it is crucial for the maintenance of mitochondrial integrity and function. The critical roles of autophagy in pancreatic β-cell structure and function have been clearly shown. Furthermore, morphological abnormalities and decreased function of mitochondria have been observed in autophagy-deficient β-cells, suggesting the importance of β-cell mitophagy. However, the role of authentic mitophagy in β-cell function has not been clearly demonstrated, as mice with pancreatic β-cell-specific disruption of Parkin, one of the most important players in mitophagy, did not exhibit apparent abnormalities in β-cell function or glucose homeostasis. Instead, the role of mitophagy in pancreatic β-cells has been investigated using β-cell-specific Tfeb-knockout mice (TfebΔβ-cell mice); Tfeb is a master regulator of lysosomal biogenesis or autophagy gene expression and participates in mitophagy. TfebΔβ-cell mice were unable to adaptively increase mitophagy or mitochondrial complex activity in response to high-fat diet (HFD)-induced metabolic stress. Consequently, TfebΔβ-cell mice exhibited impaired β-cell responses and further exacerbated metabolic deterioration after HFD feeding. TFEB was activated by mitochondrial or metabolic stress-induced lysosomal Ca2+ release, which led to calcineurin activation and mitophagy. After lysosomal Ca2+ release, depleted lysosomal Ca2+ stores were replenished by ER Ca2+ through ER→lysosomal Ca2+ refilling, which supplemented the low lysosomal Ca2+ capacity. The importance of mitophagy in β-cell function was also demonstrated in mice that developed β-cell dysfunction and glucose intolerance after treatment with a calcineurin inhibitor that hampered TFEB activation and mitophagy.

DOI: https://doi.org/10.1038/s12276-023-01055-4