bims-midtic 2023-11-26 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023–11–26
thirteen papers selected by
Omkar Joshi, Turku Bioscience

Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
Mitochondrial phosphoproteomes are functionally specialized across tissues.
Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.
Mitophagy suppression by miquelianin-rich lotus leaves extract induces "beiging" of white fat via AMPK/DRP1-PINK1/PARKIN signaling axis.
Carnation Italian Ringspot Virus p36 Expression Induces Mitochondrial Fission and Respiratory Chain Complex Impairment in Yeast.
c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.
Mfn2 regulates mitochondria-associated ER membranes to affect PCOS oocyte development.
Higher matrix stiffness promotes VSMC senescence by affecting mitochondria-ER contact sites and mitochondria/ER dysfunction.
Inhibition of PDGFRβ alleviates endothelial cell apoptotic injury caused by DRP-1 overexpression and mitochondria fusion failure after mitophagy.
Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.
Expanding roles of BCL-2 proteins in apoptosis execution and beyond.
Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.

Cell Rep. 2023 Nov 23. pii: S2211-1247(23)01484-5. [Epub ahead of print]42(12): 113472

Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.

Qixin Chen, Liu-Yi Liu, Zhiqi Tian, Zhou Fang, Kang-Nan Wang, Xintian Shao, Chengying Zhang, Weiwei Zou, Fiona Rowan, Kangqiang Qiu, Baohua Ji, Jun-Lin Guan, Dechang Li, Zong-Wan Mao, Jiajie Diao.

  Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs. By combining mtGLP with structured illumination microscopy to monitor mitochondrial dynamics, we discover the formation of nucleoid condensates in damaged mitochondria. We further reveal that nucleoid condensates promoted the peripheral fission of damaged mitochondria via asymmetric segregation. Through simulations, we find that the peripheral fission events occurred when the nucleoid condensates interacted with the highly curved membrane regions at the two ends of the mitochondria. Overall, we show that mitochondrial nucleoid condensates utilize peripheral fission to maintain mitochondrial homeostasis.

Keywords:  CP: Cell biology; chemical biology

DOI:  https://doi.org/10.1016/j.celrep.2023.113472
Nat Metab. 2023 Nov 20.

Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.

Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang, Jian-Guo Chen.

Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.

DOI: https://doi.org/10.1038/s42255-023-00924-6
Life Sci Alliance. 2024 Feb;pii: e202302147. [Epub ahead of print]7(2):

Mitochondrial phosphoproteomes are functionally specialized across tissues.

Fynn M Hansen, Laura S Kremer, Ozge Karayel, Isabell Bludau, Nils-Göran Larsson, Inge Kühl, Matthias Mann.

Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins (mitophos.de). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.

DOI: https://doi.org/10.26508/lsa.202302147
Poult Sci. 2023 Oct 28. pii: S0032-5791(23)00766-6. [Epub ahead of print]103(1): 103247

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.

Chen Yang, Pei Luo, You-Tian Yang, Xin-Liang Fu, Bing-Xin Li, Xu Shen, Dan-Ning Xu, Yun-Mao Huang, Yun-Bo Tian, Wen-Jun Liu.

  The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.

Keywords:  Drp1; PINK1; granulosa cells; heat stress; mitophagy

DOI:  https://doi.org/10.1016/j.psj.2023.103247
J Sci Food Agric. 2023 Nov 22.

Mitophagy suppression by miquelianin-rich lotus leaves extract induces "beiging" of white fat via AMPK/DRP1-PINK1/PARKIN signaling axis.

Zhenyu Wang, Tian Yang, Maomao Zeng, Zhaojun Wang, Qiuming Chen, Jie Chen, Mark Christian, Zhiyong He.

   BACKGROUND: Lotus (Nelumbo nucifera) leaf has been described to have anti-obesity activity, but the role of white fat "browning" or "beiging" in its beneficial metabolic actions remains unclear. Here, 3T3-L1 cells and high-fat-diet (HFD)-fed mice were used to evaluate the effects of miquelianin-rich lotus leaf extract (LLE) on white-to-beige fat conversion and its regulatory mechanisms.
RESULTS: Treatment with LLE increased mitochondrial abundance, mitochondrial membrane potential, and NAD+ /NADH ratio in 3T3-L1 cells, suggesting its potential in promoting mitochondrial activity. qPCR and/or Western blotting analysis confirmed that LLE induced the expression of beige fat-enriched gene signatures (e.g., Sirt1, Cidea, Dio2, Prdm16, Ucp1, Cd40, Cd137, Cited1) and mitochondrial biogenesis-related markers (e.g., Nrf1, Cox2, Cox7a, Tfam) in 3T3-L1 cells and inguinal white adipose tissue (iWAT) of HFD-fed mice. Furthermore, we found that LLE treatment inhibited mitochondrial fission protein DRP1 and blocked mitophagy markers such as PINK1, PARKIN, BECLIN1, and LC-3B. Chemical inhibition experiments revealed that AMPK/DRP1 signaling was required for LLE-induced beige fat formation via suppressing PINK1/PARKIN/mitophagy.
CONCLUSION: Our data reveal a novel mechanism underlying the anti-obesity effect of LLE, namely the induction of white fat beiging via AMPK/DRP1/mitophagy signaling. This article is protected by copyright. All rights reserved.

Keywords:  AMPK/DRP1; Beige fat; Lotus leaf extracts; Mitochondrial biogenesis; Mitophagy

DOI:  https://doi.org/10.1002/jsfa.13143
Int J Mol Sci. 2023 Nov 10. pii: 16166. [Epub ahead of print]24(22):

Carnation Italian Ringspot Virus p36 Expression Induces Mitochondrial Fission and Respiratory Chain Complex Impairment in Yeast.

Giuseppe Petrosillo, Angelo De Stradis, Domenico Marzulli, Luisa Rubino, Sergio Giannattasio.

  Positive-strand RNA virus replication invariably occurs in association with host cell membranes, which are induced to proliferate and rearrange to form vesicular structures where the virus replication complex is assembled. In particular, carnation Italian ringspot virus (CIRV) replication takes place on the mitochondrial outer membrane in plant and yeast cells. In this work, the model host Saccharomyces cerevisiae was used to investigate the effects of CIRV p36 expression on the mitochondrial structure and function through the determination of mitochondrial morphology, mitochondrial respiratory parameters, and respiratory chain complex activities in p36-expressing cells. CIRV p36 ectopic expression was shown to induce alterations in the mitochondrial network associated with a decrease in mitochondrial respiration and the activities of NADH-cyt c, succinate-cyt c (C II-III), and cytochrome c oxidase (C IV) complexes. Our results suggest that the decrease in respiratory complex activity could be due, at least in part, to alterations in mitochondrial dynamics. This yeast-based model will be a valuable tool for identifying molecular targets to develop new anti-viral strategies.

Keywords:  (+)RNA virus; CIRV; mitochondria; p36; respiratory complex; yeast

DOI:  https://doi.org/10.3390/ijms242216166
Antioxidants (Basel). 2023 Nov 16. pii: 2007. [Epub ahead of print]12(11):

c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.

Alexis Martinez, Cristian M Lamaizon, Cristian Valls, Fabien Llambi, Nancy Leal, Patrick Fitzgerald, Cliff Guy, Marcin M Kamiński, Nibaldo C Inestrosa, Brigitte van Zundert, Gonzalo I Cancino, Andrés E Dulcey, Silvana Zanlungo, Juan J Marugan, Claudio Hetz, Douglas R Green, Alejandra R Alvarez.

  The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.

Keywords:  amyotrophic lateral sclerosis; apoptosis; c-Abl; endoplasmic reticulum stress; mitochondrial fusion; mitofusin 2

DOI:  https://doi.org/10.3390/antiox12112007
Endocr Connect. 2023 Nov 01. pii: EC-23-0343. [Epub ahead of print]

Mfn2 regulates mitochondria-associated ER membranes to affect PCOS oocyte development.

Xiuhua Liao, Suqin Zhu, Shumin Qiu, Hua Cao, Wenwen Jiang, Huiling Xu, Yan Sun, Beihong Zheng.

This study aimed to investigate the role of mitochondrial-related protein Mfn2 in polycystic ovary syndrome (PCOS) and its impact on oocyte development. The pathological features of PCOS model mice were confirmed by HE staining and immunohistochemistry. The expression of Mfn2 and mitochondrial-related proteins in PCOS oocytes and granulosa cells was detected by qRT-PCR and Western blot. Mitochondrial quantity was measured by mito-tracker staining, and the structure of Mitochondria-associated ER membranes (MAMs) was observed by transmission electron microscopy. The results showed that Mfn2 was significantly downregulated in PCOS oocytes and granulosa cells, and its expression was inhibited in oocytes at different developmental stages. Moreover, the structure of MAMs was also disrupted. Downregulation of Mfn2 expression led to a reduction in mitochondrial quantity in oocytes and granulosa cells, as well as disruption of MAMs structure, while overexpression of Mfn2 had the opposite effect. In conclusion, this study indicates that Mfn2 affects the development of PCOS oocytes by regulating MAMs and may be involved in maintaining the stability of MAMs structure and function, thereby affecting mitochondrial quantity and function. These findings provide new insights into the pathogenesis and treatment of PCOS.

DOI: https://doi.org/10.1530/EC-23-0343
FASEB J. 2023 Dec;37(12): e23318

Higher matrix stiffness promotes VSMC senescence by affecting mitochondria-ER contact sites and mitochondria/ER dysfunction.

Haipeng He, Baozhu Zeng, Xinxiang Wu, Jianfeng Hou, Yannan Wang, Yanheng Wang, Yuqing Lin, Peng Wu, Changyu Zheng, Henghui Yin, Nan Wang.

  Abdominal aortic aneurysm (AAA) is a prevalent condition characterized by the weakening and bulging of the abdominal aorta. This study aimed to investigate the impact of a stiff matrix on vascular smooth muscle cells (VSMCs) in AAA development. Bioinformatics analysis revealed that differentially expressed genes (DEGs) in VSMCs of an AAA mouse model were enriched in cellular senescence and related pathways. To simulate aging-related changes, VSMCs were cultured on stiff matrices, and compared to those on soft matrices, the VSMCs cultured on stiff matrices exhibited cellular senescence. Furthermore, the mutual distance between mitochondria and endoplasmic reticulum (ER) in VSMCs was increased, indicating altered mitochondria-endoplasmic reticulum contacts (MERCs). The observed upregulation of reactive oxygen species (ROS) levels, antioxidant gene expression, and decreased mitochondrial membrane potential suggested the presence of mitochondrial dysfunction in VSMCs cultured on a stiff matrix. Additionally, the induction of ER stress-related genes indicated ER dysfunction. These findings collectively indicated impaired functionality of both mitochondria and ER in VSMCs cultured on a stiff matrix. Moreover, our data revealed that high lipid levels exacerbated the effects of high matrix stiffness on VSMCs senescence, MERC sites, and mitochondria/ER dysfunction. Importantly, treatment with the antilipemic agent CI-981 effectively reversed these detrimental effects. These findings provide insights into the role of matrix stiffness, mitochondrial dysfunction, ER stress, and lipid metabolism in AAA development, suggesting potential therapeutic targets for intervention.

Keywords:  abdominal aortic aneurysm; cellular senescence; lipid; mitochondria-endoplasmic reticulum contact sites

DOI:  https://doi.org/10.1096/fj.202301198RR
Cell Death Dis. 2023 11 18. 14(11): 756

Inhibition of PDGFRβ alleviates endothelial cell apoptotic injury caused by DRP-1 overexpression and mitochondria fusion failure after mitophagy.

Xiaohong An, Xiao Ma, Heng Liu, Jing Song, Tiange Wei, Rongzhan Zhang, Xiao Zhan, Hongyang Li, Jia Zhou.

Kawasaki disease (KD), described as "mucocutaneous lymph node syndrome", affects infants and toddlers. Patients with KD suffer from an inflammatory cascade leading to vasculitis with a predilection for coronary arteries. While the symptoms and pathogenesis of KD have received more and more attention, the precise mechanisms are still debated. Researches show that endothelial dysfunction process in KD leads to arterial damage and affect clinical outcome. In this study, we constructed a Candida albicans water soluble fraction (CAWS)-induced KD murine model and penetrated investigating the mechanisms behind endothelial dysfunction. CAWS-induced mice presented remarkably elevated vascular endothelial cell growth factor (VEGF) levels. Abundant expression of VEGF was documented in all vessels that showed edema from acute KD. It has been reported that Platelet-derived growth factor (PDGF) co-expression normalizes VEGF-induced aberrant angiogenesis. Hyperexpression of PDGFRβ was induced in the thickened medial layer and vascular endothelium of KD mice. Masitinib (Mas) is an oral tyrosine kinase inhibitor of numerous targets, which can selectively target PDGFR signaling. We set out to explore whether Mas could regulate coronary pathology in KD. Mas administration significantly reduced the VEGF-induced endothelial cells migration. NOX4 was activated in vascular endothelial cells to produce more ROS. Mitochondrial dysregulated fission and mitophagy caused by DRP-1 overexpression precipitated the arterial endothelial cells injury. Here, mitophagy seemed to work as the driving force of DRP-1/Bak/BNIP3-dependent endothelial cells apoptosis. In summary, how mitophagy is regulated by DRP-1 under pathologic status is critical and complex, which may contribute to the development of specific therapeutic interventions in cardiovascular diseases patients, for example Masatinib, the inhibitor of PDGFRβ. FACTS AND QUESTIONS: Kawasaki disease causing systemic vasculitis, affects infants and toddlers. Coronary artery injury remains the major causes of morbidity and mortality. DRP-1 overexpression induces DRP-1/Bak/BNIP3-dependent endothelial cells apoptosis. PDGFRβ was high-expressed in the thickened medial layer of CAWS-induced KD mice. Inhibition of PDGFRβ signaling alleviates arterial endothelial cells injury.

DOI: https://doi.org/10.1038/s41419-023-06272-3
ACS Nano. 2023 Nov 22.

Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.

Zhengcong Cao, Xiao Liu, Wangqian Zhang, Keying Zhang, Luxiang Pan, Maorong Zhu, Haozhe Qin, Cheng Zou, Weizhong Wang, Cong Zhang, Yalong He, Wei Lin, Yingqi Zhang, Donghui Han, Meng Li, Jintao Gu.

  The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.

Keywords:  ALOX15; ferroptosis; glioblastoma; macrophage membrane; nanoparticle

DOI:  https://doi.org/10.1021/acsnano.3c07555
J Cell Sci. 2023 Nov 15. pii: jcs260790. [Epub ahead of print]136(22):

Expanding roles of BCL-2 proteins in apoptosis execution and beyond.

Louise E King, Lisa Hohorst, Ana J García-Sáez.

  The proteins of the BCL-2 family are known as key regulators of apoptosis, with interactions between family members determining permeabilisation of the mitochondrial outer membrane (MOM) and subsequent cell death. However, the exact mechanism through which they form the apoptotic pore responsible for MOM permeabilisation (MOMP), the structure and specific components of this pore, and what roles BCL-2 proteins play outside of directly regulating MOMP are incompletely understood. Owing to the link between apoptosis dysregulation and disease, the BCL-2 proteins are important targets for drug development. With the development and clinical use of drugs targeting BCL-2 proteins showing success in multiple haematological malignancies, enhancing the efficacy of these drugs, or indeed developing novel drugs targeting BCL-2 proteins is of great interest to treat cancer patients who have developed resistance or who suffer other disease types. Here, we review our current understanding of the molecular mechanism of MOMP, with a particular focus on recently discovered roles of BCL-2 proteins in apoptosis and beyond, and discuss what implications these functions might have in both healthy tissues and disease.

Keywords:  Apoptosis; Apoptotic pore; BAX; BCL2; MOMP; Mitochondria

DOI:  https://doi.org/10.1242/jcs.260790
JCI Insight. 2023 Nov 22. pii: e174290. [Epub ahead of print]8(22):

Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.

Kun Jia, Jing Tian, Tienju Wang, Lan Guo, Zhenyu Xuan, Russell H Swerdlow, Heng Du.

  Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid β 42 (Aβ42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized Aβ (humanized Aβ-knockin [hAβ-KI] mice) confirmed the association of increased intramitochondrial sequestration of Aβ42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk-bearing context. Also, in comparison with global cerebral Aβ, intramitochondrial Aβ was relatively preserved from activated microglial phagocytosis in aged hAβ-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Aβ sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial Aβ, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.

Keywords:  Aging; Alzheimer disease; Mitochondria; Mouse models; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.174290