Mitochondrial aconitase 1 regulates age‐related memory impairment via autophagy/mitophagy‐mediated neural plasticity in middle‐aged flies

Abstract

Age-related memory impairment (AMI) refers to a significant decrease in learning and memory ability with age (Gkikas et al., 2014).Approximately 40% of people over 60 years of age experience AMI.Notably, AMI results in decreased acumen to encode working memories of new events or facts (Klencklen et al., 2017). Moreover, AMI also can appear in middle age (Kwon et al., 2016). The known causes of AMI in humans are age-related changes in the levels of cortisol,

A brain-wide form of presynaptic active zone plasticity orchestrates resilience to brain aging in Drosophila

“…We collected brain samples of wild type ( wt ) at the following ages: 1-day-old (1d), 10d, 20d, 30d, 40d, 50d, 60d, and 70d, for quantitative western blot analysis monitoring a spectrum of pre- and postsynaptic proteins: BRP [ 37 , 39 ], (m)Unc13 family protein Unc13A [ 34 ], synaptic vesicle protein Synapsin (Syn) [ 43 ], SNARE complex core component Syntaxin (Syx) [ 44 ], the homolog of mammalian scaffold protein PSD95 Discs large (Dlg1) [ 45 ], as well as the crucial autophagy protein Atg8a, which is regulated by the aging process [ 46 ]. Indeed, BRP, Unc13A, Syn, and Dlg1 first increased almost linearly to arrive at a plateau at 30d to 40d (“early aging”) ( Fig 1B–1F ), while the ratios between activated, lipidated Atg8a (Atg8a-II) and inactive, unlipidated Atg8a (Atg8a-I) showed a clear trend of gradual reduction during early aging ( Fig 1B and 1H ), consistent with previous reports [ 10 , 35 , 46 ]. Thereafter, however, the levels of these proteins dropped gradually with further advanced aging ( Fig 1A–1F ).…”

“…Efficient mitochondrial electron transport and autophagy in turn are coupled to sleep regulation [ 82 , 83 ]. Moreover, mitochondrial functionality bidirectionally regulates early aging-associated PreScale-type plasticity revealed by BRP levels [ 35 ], and autophagy defects trigger PreScale in a non-cell-autonomous manner [ 84 ]. Thus, we speculate that Spd might delay the onset of early aging-associated sleep pattern changes and memory decline through its improvements of mitochondrial functions and autophagy, while making PreScale dispensable.…”

“…Notably, Spd facilitates memory formation in mid-aged 30-day-old animals [ 10 ] and extends lifespan [ 15 ], and, at the same time attenuates the age-associated emergence of PreScale [ 8 ]. Similarly, bidirectional regulation of mitochondrial Aconitase 1 was found to modulate PreScale-type plasticity in conjunction with its effects on lifespan and age-associated memory decline [ 35 ]. Thus, BRP-driven PreScale seems to operate at a critical intersection of different aspects of brain aging.…”

A brain-wide form of presynaptic active zone plasticity orchestrates resilience to brain aging in Drosophila

“…To address our question, we collected brain samples of wildtype ( wt ) at the following ages: 1-day-old (1d), 10d, 20d, 30d, 40d, 50d, 60d and 70d, for quantitative Western blot analysis monitoring a spectrum of pre- and postsynaptic proteins: BRP (Kittel et al, 2006; Wagh et al, 2006), (m)Unc13 family protein Unc13A (Böhme et al, 2016), synaptic vesicle protein Synapsin (Syn) (Klagges et al, 1996), SNARE complex core component Syntaxin (Syx) (Schulze et al, 1995), the homolog of mammalian scaffold protein PSD95 Discs large (Dlg1) (Woods and Bryant, 1991), as well as the crucial autophagy protein Atg8a which is regulated by the aging process (Simonsen et al, 2008). Indeed, BRP, Unc13A, Syn and Dlg1 first increased almost linearly to arrive at a plateau at 30d to 40d (“early aging”) (Figures 1B-1F), while the ratios between activated, lipidated Atg8a (Atg8a-II) and inactive, un-lipidated Atg8a (Atg8a-I) showed a clear trend of gradual reduction during early aging (Figures 1B and 1H), consistent with previous reports (Simonsen et al, 2008; Gupta et al, 2013; Cho et al, 2021). Thereafter, however, the levels of these proteins dropped gradually with further advanced aging (Figures 1A-1F).…”

“…Efficient mitochondrial electron transport and autophagy in turn are coupled to sleep regulation (Kempf et al, 2019; Bedont et al, 2021). Moreover, mitochondrial functionality bidirectionally regulates early aging-associated PreScale-type plasticity revealed by BRP levels (Cho et al, 2021), and autophagy defects trigger PreScale in a non-cell autonomous manner (Bhukel et al, 2019). Thus, we speculate that Spd might delay the onset of early aging-associated sleep pattern changes and memory decline through its improvements of mitochondrial functions and autophagy and the consequent suppression of PreScale.…”