. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019 Mar;22(3):401-412. Epub 2019 Feb 11 PubMed.


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  1. This is an outstanding study. It not only adds significant evidence supporting a critical role of mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease, but also specifically suggests mitophagy as a promising therapeutic target for AD. 

    Different from the previous neuron-centric study of mitochondrial (dys)function in AD, it is most interesting and significant that this study demonstrated that mitophagy is also impaired in the microglia in AD mouse brain, and that mitophagy stimulation enhances the phagocytic efficiency of microglia to clear amyloid plaques along with mitigation of NLRP3/caspase-1-dependent neuroinflammation.

    While the authors suggested that enhanced phagocytic efficiency in microglia is likely due to the restored supply of required energy by improved mitochondrial homeostasis, detailed mechanisms warrant further investigation. Overall, the study demonstrated the neuroprotective and restorative potential of mitophagy enhancement in AD.

    However, since mitochondrial mass is reduced in pyramidal neurons in AD (Hirai et al., 2001), and current evidence supports the notion of impaired mitochondrial biogenesis in AD (Qin et al., 2009; Sheng et al., 2012), the pursuit of mitophagy enhancers alone as a therapeutic may be limited.


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    View all comments by Wenzhang Wang
  2. This paper from Fang et al. represents an impressive amount of work examining the interplay between dysfunctional mitophagy, inflammation, and AD pathologies in multiple disease models. These data add to multiple studies implicating dysfunctional mitophagy in PD (reviewed in (reviewed in McWilliams and Muqit, 2017), a growing number of papers demonstrating a number of FTD/ALS genes are involved in the mitophagy process, such as TBK1, SQSTM, OPTN and VCP (Karbowski and Youle, 2011; Heo et al., 2015; Kim et al., 2013), and a few recent studies suggesting a role for mitophagy in AD (Sorrentino, et al., 2017; Du et al., 2017; Checler et al., 2017; Martín-Maestro et al., 2016). Thus, mitophagy is emerging as a crucial mechanism across multiple neurodegenerative diseases.

    Neurons rely quasi-exclusively on mitochondria for ATP production, thus the selective clearance of damaged mitochondria by mitophagy is critical to maintain the bioenergetic integrity of the cell and prevent the accumulation of damaged mitochondria and toxic reactive oxygen species. The reliance on mitochondria also means mitophagy is a rare event, and most studies require overexpression and induction of mitophagy using mitochondrial uncoupling agents that artificially induce mitochondrial depolarization. A strength of this study is the cross-species analysis of basal mitophagy in multiple in vitro and in vivo models. 

    The work raises some interesting questions. There are multiple pathways coordinating mitochondrial integrity, and it will be important to identify the specific mitophagy pathway(s) that is/are dysfunctional in AD. The PINK1-dependent pathway is the most well-characterized mechanism for the induction and execution of mitophagy, however PINK1 knockout mice do not have defective mitophagy (McWilliams et al., 2018), and so it is intriguing that such widespread alterations in basal mitophagy are observed in AD models. The PINK1 pathway could be explored more extensively in these models by using alternative methods, such as mtQC mitophagy mice reporters (McWilliams et al., 2018), and by examining (for example) the levels of phosphorylated ubiquitin at serine 65, which is a substrate of PINK1 precluding the recruitment of Parkin to damaged mitochondria. It would also be important to study mitochondrial biogenesis in more detail, especially as PGC1a levels seem to be reduced in their AD models. Finally, it would be interesting to know whether the defects observed in hippocampus also occur in other brain regions in their disease models.

    A number of studies have suggested an interplay of neuronal and glial cells to orchestrate mitophagy in a transcellular manner (Davis et al., 2014), yet this paper suggests a new role for mitophagy in enhancing a dual role for microglia: the phagocytic clearance of Aβ plaques and the release of pro-inflammatory cytokines. The role of the connected network of neurons and glial cells will need to be studied in more detail in AD and in other neurodegenerative conditions.

    Together, these data add to a growing body of evidence highlighting the importance of mitophagy across multiple diseases. Future mechanistic studies will highlight the potential of this pathway for therapeutic targeting.


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    View all comments by Selina Wray
  3. We agree with Xiongwei Zhu and Wenzhang Wang on significant evidence supporting a critical role of mitochondrial dysfunction in Alzheimer's disease. We have pursued this premise to conduct IRB-approved placebo controlled clinical trials in human LOAD.

    Our clinical experience and published findings on transcranial and intraocular infrared photobiomodulation suggests that increasing ATP activation through stimulating Cytochrome C Oxidase in the mitochondria results in improved cognitive and behavioral functioning in adults with dementia and Parkinson's disease. Recent AD animal model data showed this type of noninvasive stimulation improved praxis memory, motor behavior, reduced Aβ42 and p-tau, confers neuroprotection, and significantly increased VEGF production. Expanded human clinical trials are now underway at Baylor Research Institute (Temple, Texas) and Quietmind Foundation (Elkins Park, Pennsylvania) to evaluate the impact of self-administered, twice-daily, six-minute, transcranial and intraocular exposure to near infrared photobiomodulation.

    Jason Huang also contributed to this comment.


    . Photobiomodulation with Near Infrared Light Helmet in a Pilot, Placebo Controlled Clinical Trial in Dementia Patients Testing Memory and Cognition. J Neurol Neurosci. 2017;8(1) Epub 2017 Feb 28 PubMed.

    . Non-invasive infra-red therapy (1072 nm) reduces β-amyloid protein levels in the brain of an Alzheimer's disease mouse model, TASTPM. J Photochem Photobiol B. 2013 Jun 5;123:13-22. Epub 2013 Mar 22 PubMed.

    . Low-Intensity Light Therapy (1068nm) Protects CAD Neuroblastoma Cells from β-Amyloid-Mediated Cell Death. Biol Med 2014

    . Enhancement of cutaneous immune response to bacterial infection after low-level light therapy with 1072 nm infrared light: a preliminary study. J Photochem Photobiol B. 2011 Dec 2;105(3):175-82. Epub 2011 Sep 6 PubMed.

    View all comments by Trent Nichols
  4. Aging, the most important risk factor for AD, is linked to reductions in mitophagy. This is a remarkable and outstanding paper since it ties tau phosphorylation and amyloid pathology to mitochondrial dysfunction and defective mitophagy. These findings shed light on the underlying mechanisms of mitophagy and emphasize the importance of developing new therapeutic strategies targeting mitochondrial dysfunction in AD and other neurodegenerative diseases.

    Cellular energy is mainly produced via mitochondrial oxidative phosphorylation (OXPHOS). Impaired mitochondrial function is a major contributor to human pathology and plays a critical role in the onset and progression of neurodegenerative diseases. Accumulation of misfolded proteins, downregulation of mitochondrial electron transport chain activity, axonopathy, and unbalanced mitochondrial dynamics are prevalent features of mitochondrial dysfunction.

    Aberrant mitochondrial function has been linked to the pathogenesis of Alzheimer’s disease (AD), which is characterized by the formation of amyloid β (Aβ) plaques and hyperphosphorylated tau in the form of intraneuronal neurofibrillary tangles (Perez Ortiz and Swerdlow, 2019). Accumulation of dysfunctional mitochondria diminishes ATP production and disrupts the redox balance, which initiates oxidative damage, mitochondrial deficits, and subsequent amyloid pathology. Mitochondrial accumulation of Aβ and APP (mediated by the TOM-TIM protein complexes) was detected in the frontal cortices and hippocampi of AD patients and transgenic AD mice (Anandatheerthavarada et al., 2003; Lustbader et al., 2004; Devi et al., 2006). Overexpression of Aβ resulted in the perturbation of mitochondrial dynamics with concomitant abnormal mitochondrial morphology and distribution in vitro and in Tg2576 mice (Wang et al., 2008; Calkins et al., 2011). Changes in the concentration of the mitochondrial fission and fusion-related proteins, morphological structure, and localization have been reported in fibroblasts and subjects with sporadic AD (Wang et al., 2008; Manczak et al., 2011; Martin-Maestro et al., 2017). Furthermore, an early and progressive accumulation of Aβ (mainly Aβ1-42) within mitochondria leads to synaptic mitochondrial dysfunction in transgenic mice overexpressing APP/Aβ (Du et al., 2010). 

    Selective degradation of mitochondria by autophagy (mitophagy) is part of the quality-control system of cells and is essential to maintain mitochondrial homeostasis. Disruption of mitophagy results in mitochondrial membrane depolarization, ATP depletion, and oxidative damage. PTEN-induced putative kinase 1 (PINK1) accumulates on dysfunctional mitochondria and its kinase activity is required for the translocation to mitochondria of parkin (a cytosolic E3 ubiquitin) to mediate the autophagic removal of damaged mitochondria. Mutations in PINK1 and parkin prevent PINK1 recruitment of parkin into mitochondria and are responsible for autosomal-recessive and some sporadic forms of Parkinson's disease (PD). Clinical and experimental evidence has demonstrated that mitophagy is compromised in AD. Parkin-mediated mitophagy was significantly activated in cultured cortical neurons derived from human APP transgenic mice and postmortem hippocampal tissue specimens from AD patients (Ye et al., 2015). 

    Which are the effects of tau and Aβ on mitophagy quality control? Impaired mitophagy was observed in N2a cells transfected with wild-type and P301L mutant human tau and transgenic C. elegans (Cummins et al., 2019). Expression of tau also disrupted the translocation of Parkin to mitochondria through a mitochondrial membrane potential-independent mechanism. Aβ accumulation in synaptosomal mitochondria of 5xFAD mice decreased axonal mitochondrial length, altered mitochondrial dynamics, and increased Parkin-mediated mitophagy (Wang et al., 2016). Overexpression into the hippocampi of mice of either PINK1 or parkin, the primary enzymes implicated in mediating mitophagy, can exert beneficial effects on the neuropathological hallmarks of AD, Aβ plaques, and neurofibrillary tangles (Khandelwal et al., 2011; Du et al., 2017). Perturbed mitochondrial proteostasis and activated mitophagy have been reported in transgenic C. elegans, 3xTgAD mice, and brain tissue from AD patients. Treatment with nicotinamide riboside, which increases NAD+ levels and activates sirtuins, significantly reduced Aβ aggregates and associated proteotoxicity (Sorrentino et al., 2017). More recently, in a well-conducted study, Bohr’s group showed alterations in mitochondrial function and changes in the immunoreactivity of mitophagy-associated proteins in both brain biopsies and iPSC-derived neurons from AD patients (Fang et al., 2019). The levels of 5' AMP-activated protein kinase, which leads to excessive mitochondrial fission and ATP depletion, were increased in the hippocampi of patients with AD. They showed that pharmacologic or genetic activation of mitophagy significantly mitigated cognitive deficits and Aβ-induced toxicity in APP/PS1 AD mice. Mitophagy induction also reduced tau hyperphosphorylation and improved memory deficits and cognitive decline in nematodes and mice, respectively. Pharmacological restoration of mitophagy promoted microglial phagocytosis and mitigated neuroinflammation in a double-transgenic mouse model of AD.


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    View all comments by M. Flint Beal
  5. We share the view of Drs. Tapias and Beal that misfolded proteins such as Aβ and tau impair all aspects of mitochondrial functions. In fact, we have a long-standing interest in how Aβ and tau impair neuronal functions, dating back to 2005 when we combined a proteomic with a functional analysis showing impairments to the OXPHOS system (David et al., 2005). 

    What is relevant in the context of how mitochondrial function is impaired under pathological conditions is a study which we recently performed that adds another layer to mitochondrial dysfunctions and how the cell responds to it. We developed a protocol in primary hippocampal cultures that combines the photosensitizer mito-KillerRed with fluorescent biosensors and photoactivatable GFP. We found in both the soma and dendrites that by quarantining mitochondria, neurons restrict the local increase in mitochondria-derived reactive oxygen species and the decrease in ATP production to the damaged compartment.

    Interestingly, although the cytosol of both the soma and dendrites became oxidized after mito-KillerRed activation, dendrites were more sensitive to the oxidative insult. Importantly, the impaired mitochondria exhibited decreased motility and fusion, thereby avoiding the spread of oxidation throughout the neuron. These results establish how neurons manage oxidative damage and increase our understanding about the somatodendritic regulation of mitochondrial function after a local oxidative insult (Grimm et al., 2018). 


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    . Local Oxidative Damage in the Soma and Dendrites Quarantines Neuronal Mitochondria at the Site of Insult. iScience. 2018 Aug 31;6:114-127. Epub 2018 Jul 23 PubMed.

    View all comments by Jürgen Götz

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  1. Could Disposing of Damaged Mitochondria Treat Alzheimer’s Disease?