bims-tofagi 2024-03-10 papers

on Mitophagy

Issue of 2024–03–10
nine papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea

An unexpected journey for BNIP3.
Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.
The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.
WDR83/MORG1 inhibits RRAG GTPase-MTORC1 signaling to facilitate basal autophagy.
CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.
Advances in the study of mitophagy in osteoarthritis.
PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.
The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
Prodromal Parkinson disease signs are predicted by a whole-blood inflammatory transcriptional signature in young Pink1-/- rats.

Autophagy. 2024 Mar 06. 1-2

An unexpected journey for BNIP3.

José M Delgado, Christopher J Shoemaker.

  Mitophagy is a cellular process that enables the selective degradation of damaged, dysfunctional, or superfluous mitochondria. During mitophagy, specific proteins recognize and tag mitochondria for degradation. These tagged mitochondria are engulfed by specialized structures called phagophores that then mature into autophagosomes/mitophagosomes. Mitophagosomes subsequently transport their mitochondrial cargo to lysosomes, where the mitochondria are broken down and recycled. While the PINK1-PRKN-dependent mitophagy pathway is well understood, mitophagy can also occur independently of this pathway. BNIP3 and BNIP3L/NIX, paralogous membrane proteins on the outer mitochondrial membrane (OMM), serve as ubiquitin-independent mitophagy receptors. Historically, BNIP3 regulation was thought to be primarily transcriptional through HIF1A (hypoxia inducible factor 1 subunit alpha). However, recent work has revealed a significant post-translational dimension, highlighting the strong role of the ubiquitin-proteasome system (UPS) in BNIP3 regulation. With these emerging concepts in mind, we aimed to develop a unified understanding of how steady-state levels of BNIP3 are established and maintained and how this regulation governs underlying cell physiology.

Keywords:  BNIP3; EMC; ER membrane protein complex; NIX; membrane trafficking; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2312038
Autophagy. 2024 Mar 08. 1-2

Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.

Zhangyuan Yin, Daniel J Klionsky.

  The selective clearance of unwanted, damaged or dangerous components by macroautophagy/autophagy is critical for maintaining cellular homeostasis in organisms from yeast to humans. In recent years, significant progress has been made in understanding how phagophores selectively sequester specific cargo. Nevertheless, a fundamental question remains: Can distinct selective autophagy programs simultaneously operate within the same cell? A recent study from the Baehrecke lab has unveiled a developmentally programmed Pink1-dependent reticulophagy process in the Drosophila intestine. Furthermore, this study demonstrated that autophagy differentially clears mitochondria and ER in the same cell under the regulation of Pink1 through different E3 ubiquitin ligases, highlighting the need for further exploration in understanding the complexity of autophagic substrate selection and crosstalk between diverse autophagy programs.

Keywords:  Autophagy receptor; Keap1; Pink1; mitophagy; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2024.2323294
Exp Mol Med. 2024 Mar 05.

The Mst1/2-BNIP3 axis is required for mitophagy induction and neuronal viability under mitochondrial stress.

Dae Jin Jeong, Jee-Hyun Um, Young Yeon Kim, Dong Jin Shin, Sangwoo Im, Kang-Min Lee, Yun-Hee Lee, Dae-Sik Lim, Donghoon Kim, Jeanho Yun.

Mitophagy induction upon mitochondrial stress is critical for maintaining mitochondrial homeostasis and cellular function. Here, we found that Mst1/2 (Stk3/4), key regulators of the Hippo pathway, are required for the induction of mitophagy under various mitochondrial stress conditions. Knockdown of Mst1/2 or pharmacological inhibition by XMU-MP-1 treatment led to impaired mitophagy induction upon CCCP and DFP treatment. Mechanistically, Mst1/2 induces mitophagy independently of the PINK1-Parkin pathway and the canonical Hippo pathway. Moreover, our results suggest the essential involvement of BNIP3 in Mst1/2-mediated mitophagy induction upon mitochondrial stress. Notably, Mst1/2 knockdown diminishes mitophagy induction, exacerbates mitochondrial dysfunction, and reduces cellular survival upon neurotoxic stress in both SH-SY5Y cells and Drosophila models. Conversely, Mst1 and Mst2 expression enhances mitophagy induction and cell survival. In addition, AAV-mediated Mst1 expression reduced the loss of TH-positive neurons, ameliorated behavioral deficits, and improved mitochondrial function in an MPTP-induced Parkinson's disease mouse model. Our findings reveal the Mst1/2-BNIP3 regulatory axis as a novel mediator of mitophagy induction under conditions of mitochondrial stress and suggest that Mst1/2 play a pivotal role in maintaining mitochondrial function and neuronal viability in response to neurotoxic treatment.

DOI: https://doi.org/10.1038/s12276-024-01198-y
Autophagy. 2024 Mar 07. 1-2

WDR83/MORG1 inhibits RRAG GTPase-MTORC1 signaling to facilitate basal autophagy.

Athanasios Kournoutis, Trond Lamark, Terje Johansen, Yakubu Princely Abudu.

  Macroautophagy/autophagy is a conserved lysosomal degradation process composed of both selective and nonselective degradation pathways. The latter occurs upon nutrient depletion. Selective autophagy exerts quality control of damaged organelles and macromolecules and is going on also under nutrient-replete conditions. Proper regulation of autophagy is vital for cellular homeostasis and prevention of disease. During nutrient availability, autophagy is inhibited by the MTORC1 signaling pathway. However, selective, basal autophagy occurs continuously. How the MTORC1 pathway is fine-tuned to facilitate basal constitutive autophagy is unclear. Recently, we identified the WD-domain repeat protein WDR83/MORG1 as a negative regulator of MTORC1 signaling allowing basal, selective autophagy. WDR83 interacts with both the Ragulator and active RRAG GTPases to prevent recruitment of the MTORC1 complex to the lysosome. Consequently, WDR83 depletion leads to hyperactivation of the MTORC1 pathway and a strong decrease in basal autophagy. As a consequence of WDR83 depletion cell proliferation and migration increase and low levels of WDR83 mRNA are correlated with poor prognosis for several cancers.

Keywords:  Autophagy; MORG1; MTORC1; RRAG GTPases; SQSTM1/p62; breast cancer

DOI:  https://doi.org/10.1080/15548627.2024.2322457
Autophagy. 2024 Mar 06. 1-25

CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.

Prakash P Praharaj, Srimanta Patra, Amruta Singh, Debasna P Panigrahi, Hwa Y Lee, Mohammad F Kabir, Muhammad K Hossain, Samir K Patra, Birija S Patro, Shankargouda Patil, Daniel J Klionsky, Han J Chae, Sujit K Bhutia.

  Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.

Keywords:  Clusterin; PPARGC1A/PGC1α; mitochondrial biogenesis; mitophagy; mitophagy-associated cell death

DOI:  https://doi.org/10.1080/15548627.2024.2309904
J Zhejiang Univ Sci B. 2024 Mar 15. pii: 1673-1581(2024)03-0197-15. [Epub ahead of print]25(3): 197-211

Advances in the study of mitophagy in osteoarthritis.

Hong Cao, Xuchang Zhou, Bowen Xu, Han Hu, Jianming Guo, Miao Wang, Nan Li, Zou Jun.

  Osteoarthritis (OA), characterized by cartilage degeneration, synovial inflammation, and subchondral bone remodeling, is among the most common musculoskeletal disorders globally in people over 60 years of age. The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process. Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism. Therefore, maintaining mitochondrial homeostasis is an important strategy to mitigate OA. Mitophagy is a vital process for autophagosomes to target, engulf, and remove damaged and dysfunctional mitochondria, thereby maintaining mitochondrial homeostasis. Cumulative studies have revealed a strong association between mitophagy and OA, suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA. By reviewing the literature on mitophagy and OA published in recent years, this paper elaborates the potential mechanism of mitophagy regulating OA, thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.

Keywords:  Apoptosis; Chondrocyte; Mitochondria; Mitophagy; Osteoarthritis

DOI:  https://doi.org/10.1631/jzus.B2300402
Nat Commun. 2024 Mar 04. 15(1): 1967

PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.

Wenhao Li, Hongwei Zhu, Jinzhu Chen, Binglu Ru, Qin Peng, Jianqiang Miao, Xili Liu.

Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 in Phytophthora sojae cannot recruit PsATG8 to stressed mitochondria without PsAF5. PsAF5 deletion impairs mitophagy under ROS stress and increases the pathogen's sensitivity to H2O2, resulting in the attenuation of P. sojae virulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.

DOI: https://doi.org/10.1038/s41467-024-46290-z
Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.

Alice Lacombe, Luca Scorrano.

  The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.

Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy

DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
BMC Neurosci. 2024 Mar 04. 25(1): 11

Prodromal Parkinson disease signs are predicted by a whole-blood inflammatory transcriptional signature in young Pink1-/- rats.

Sarah A Lechner, David G S Barnett, Stephen C Gammie, Cynthia A Kelm-Nelson.

   BACKGROUND: Parkinson disease (PD) is the fastest growing neurodegenerative disease. The molecular pathology of PD in the prodromal phase is poorly understood; as such, there are no specific prognostic or diagnostic tests. A validated Pink1 genetic knockout rat was used to model early-onset and progressive PD. Male Pink1-/- rats exhibit progressive declines in ultrasonic vocalizations as well as hindlimb and forelimb motor deficits by mid-to-late adulthood. Previous RNA-sequencing work identified upregulation of genes involved in disease pathways and inflammation within the brainstem and vocal fold muscle. The purpose of this study was to identify gene pathways within the whole blood of young Pink1-/- rats (3 months of age) and to link gene expression to early acoustical changes. To accomplish this, limb motor testing (open field and cylinder tests) and ultrasonic vocalization data were collected, immediately followed by the collection of whole blood and RNA extraction. Illumina® Total RNA-Seq TruSeq platform was used to profile differential expression of genes. Statistically significant genes were identified and Weighted Gene Co-expression Network Analysis was used to construct co-expression networks and modules from the whole blood gene expression dataset as well as the open field, cylinder, and USV acoustical dataset. ENRICHR was used to identify the top up-regulated biological pathways.
RESULTS: The data suggest that inflammation and interferon signaling upregulation in the whole blood is present during early PD. We also identified genes involved in the dysregulation of ribosomal protein and RNA processing gene expression as well as prion protein gene expression.
CONCLUSIONS: These data identified several potential blood biomarkers and pathways that may be linked to anxiety and vocalization acoustic parameters and are key candidates for future drug-repurposing work and comparison to human datasets.

Keywords:  Parkinson disease; Pink1−/− ; RNA-sequencing; Rat; Whole blood

DOI:  https://doi.org/10.1186/s12868-024-00857-0