Unexpected cellular metabolism impacts on diseases DOJINDO LABORATORIES

Previous Science Note

Regulation of cellular metabolism is critical for maintaining the proper balance of energy and biomolecules within the cell. Hormones, enzymes, and other regulatory molecules control the rate of metabolic reactions. Imbalances in cellular metabolism can lead to diseases such as diabetes, cancer, and metabolic disorders. Interestingly, several findings are beginning to be reported that intracellular metabolism contributes to cellular homeostasis in unexpected ways. Today, we introduce you to three highlighted articles focusing on cellular metabolism related to TCA cycle in nucleus, Metabolic transformation, Lipid- controlled mitochondrial transfer.

TCA cycle in nucleus

Operation of a TCA cycle subnetwork in the mammalian nucleus
(Eleni Kafkia, et al., Science Avvances, 8, eabq5206, 2022)

Point of Interest
- Using ¹³C-tracer analysis, the activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes was identified in the nuclei.

- Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins.

- 2-oxoglutarate dehydrogenase, which produces succinyl-CoA, also localizes at the nucleus in mouse embryonic stem cells.

- The nuclear localization of this enzyme changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation.

Warburg-like metabolic transformation in Alzheimer’s disease

Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease
(Larissa Traxler, et al., Cell Metabolism, 34, 1248-1263, 2022)

Point of Interest
- iNs from patients with AD express cancer-associated PKM2.

- PKM2 facilitates Warburg-effect-like glycolytic reprogramming of old neurons.

- Nuclear PKM2 associates with STAT3 and HIF1α to promote neuronal fate loss in AD iNs.

- Modulation of PKM2 with shikonin restores healthy neuronal features.

Dietary lipids and mitochondria transfer

Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood
(Nicholas Borcherding, et al., Cell Metabolism, 34, 1499-1513, 2022)

Point of Interest
- Adipocytes transfer mitochondria to tissue-specific networks of cells in fat.

- Diet-induced obesity, but not aging, impairs mitochondria transfer to macrophages.

- Dietary long-chain fatty acids inhibit mitochondria uptake by macrophages.

- Macrophages limit the release of adipocyte mitochondria into blood.