Lysosomes were once viewed mainly as cellular waste disposers, but are now recognized as key hubs for nutrient sensing and metabolic signaling. Still, what lysosomes contribute metabolically inside high-demand neurons in the intact brain remains elusive.

In a new study in Life Metabolism, Prof. Yang Li and colleagues at Fudan University report that nutritional stress drives hippocampal lysosomes in mice to accumulate several tricarboxylic acid (TCA) cycle intermediates, suggesting a mobilizable subcellular buffer that could support neuronal metabolic resilience.

The team established an in vivo AAV-LysoTag/Lyso-IP workflow in the mouse hippocampus, coupled to targeted metabolomics and lipidomics. Using every-other-day fasting (EODF) as a model of intermittent energy stress, they directly profiled metabolites and lipids enriched within immunoisolated hippocampal lysosomes. The results showed that fasting induced a broad remodeling of the lysosomal metabolome. As expected, substrates consistent with increased protein and lipid breakdown accumulated, alongside lysosome-associated lipid changes such as upregulation of bis(monoacylglycero)phosphate (BMP). Notably, TCA cycle metabolites classically associated with mitochondrial metabolism, including malic acid, α-ketoglutarate (α-KG), and citric acid, were significantly elevated within lysosomes (Figure 1).

To explore where these metabolites might come from, the authors propose three, non-mutually exclusive routes: (1) mitochondrial delivery to lysosomes during starvation-associated mitochondria–lysosome crosstalk; (2) potential local interconversion supported by lysosome-associated signals of TCA enzymes including isocitrate dehydrogenase (IDH) and fumarate hydratase (FH); and (3) transporter-mediated exchange, supported by detection of the oxoglutarate carrier (OGC/SLC25A11) in LAMP1⁺ compartments. The study emphasizes that enzyme localization and inhibitor experiments are suggestive, and that future flux and functional assays will be needed to establish catalytic activity and causal transport mechanisms in situ.

Together, the work reframes lysosomes in the brain from passive degradative endpoints to dynamic metabolic nodes that may help neurons cope with fluctuating nutrient availability. Beyond providing a methodological resource for in vivo lysosome metabolomics, the findings offer testable hypotheses for neurometabolic adaptation and for disorders where lysosome function and metabolism intersect.
DOI
10.1093/lifemeta/loag005