Organelle dysfunction and its contribution to metabolic impairments in aging and age-related diseases

Heiby, Julia C.; Ori, Alessandro

doi:10.1016/j.coisb.2022.100416

Cited by 3 publications

(2 citation statements)

References 126 publications

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“…This remodeling encompasses a decrease of mitochondrial ribosomes, while respiratory chain components remain stable or increase, as in the case of Complex IV. This is consistent with broader observations of aging-induced mitochondrial changes ( 44 , 45 ). These findings based on bulk tissue measurements were corroborated by more direct analysis of the composition of mitochondria from subcellular fractions and by other age-dependent alterations of mitochondrial proteins, e.g., in detergent insolubility.…”

Section: Discussionsupporting

confidence: 92%

“…These observations based on bulk tissue measurements were corroborated by more direct analysis of the composition of mitochondria from subcellular fractions and by other age-dependent alterations of mitochondrial proteins, e.g., in detergent insolubility and sedimentation profiles. A compositional change of the brain mitochondrial proteome with age aligns with previous observations from other species (Ingram and Chakrabarti 2016), and with ultrastructural and functional alterations reported in aging and age-associated diseases (Heiby and Ori 2022). We also found that other aspects of mitochondria aging in the brain, i.e., reduced mtDNA content, were instead dependent on decreased proteasome activity, highlighting the convergence of multiple aging mechanisms in determining the levels and composition of key cellular structures such as mitochondria (Figure 6C).…”

Section: Discussionsupporting

confidence: 88%

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Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

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Protein homeostasis declines both in aging and neurodegenerative diseases, yet our understanding of how aging affects brain proteostasis is still limited. Here, we measured and integrated the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We found that aging causes a decoupling between transcript and protein levels leading to, e.g., decreased abundance of proteins enriched in basic amino acids independent of mRNA changes. Chronic proteasome impairment in vivo induces aging signatures in lysosomes and mitochondria. However, it does not recapitulate the age-related decoupling between transcripts and proteins. Instead, increased translation pausing and reduced ribosome levels reprogram protein synthesis independently of transcription. These changes in protein biogenesis likely reduce the availability of key protein complexes and contribute to the remodeling of organelles in older brains.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

Self Cite

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Editorial overview: The metabolic network

Fendt

Ralser

2022

Current Opinion in Systems Biology

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Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder

Ghoochani,

Heiby,

Rawat

et al. 2024

Preprint

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Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration.

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Organelle dysfunction and its contribution to metabolic impairments in aging and age-related diseases

Cited by 3 publications

References 126 publications

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Editorial overview: The metabolic network

Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder

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