Dataset Information

Redefining the role of the Plasmodium heme detoxification protein: From hemozoin to mitochondrial protein synthesis

ABSTRACT: Malaria blood-stage parasites digest ~80% of host cell hemoglobin within a degradative vacuole, releasing heme that is detoxified by sequestration into hemozoin crystals. Although essential for survival and a validated drug target, the mechanisms of heme biomineralization remain unclear. We studied the parasite’s Heme Detoxification Protein (HDP), previously proposed to mediate hemozoin formation, using genetic, microscopic, bioenergetic, and proteomic approaches. Endogenous tagging revealed that HDP localizes to the mitochondrion, not the vacuole. Conditional HDP inactivation had no effect on heme biomineralization, but caused mitochondrial depolarization, hypersensitivity to proguanil, and developmental arrest, which was rescued by bypassing respiratory-chain-dependent pyrimidine biosynthesis. HDP knockout abolished mitochondrial electron flow due to loss of complexes III and IV, consistent with impaired mitochondrial protein synthesis. Integration of structural modelling with quantitative proteomics placed HDP within the mitoribosomal large subunit. Here, we show that HDP is essential for mitochondrial function and does not contribute to hemozoin formation.

ORGANISM(S): Plasmodium Falciparum

SUBMITTER: Joachim M. Matz

PROVIDER: PXD073350 | JPOST Repository | Mon Jun 29 00:00:00 BST 2026

REPOSITORIES: jPOST

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	M250909_005_Slot2-28_1_38260.d.zip	Other
	M250909_006_Slot2-29_1_38261.d.zip	Other
	M250909_007_Slot2-30_1_38262.d.zip	Other
	M250909_008_Slot2-31_1_38263.d.zip	Other
	M250909_010_Slot2-32_1_38265.d.zip	Other

Items per page:

1 - 5 of 20

Similar Datasets

Project description:Mitochondrial abnormalities are commonly associated with aging-related degenerative disease and the atrophy of tissues including muscle and brain. Whether bioenergetic defect is the sole pathogenic factor has been long questioned. Lysosomal damage is another hallmark of degenerative disease. However, it is unknown whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. Here, we show that mitochondrial protein import stress, which can be induced by many forms of mitochondrial injuries, causes structural and functional damage to the yeast vacuole and its mouse counterpart, the lysosome. This effect is independent of bioenergetic defects and the production of reactive oxygen species. We found that unimported mitochondrial proteins are targeted to the vacuole for degradation in yeast. Overloading by these proteins causes V-ATPase disassembly, and vacuolar deacidification, fragmentation and membrane permeabilization. In a mouse model of mitochondrial protein import stress and muscle atrophy induced by overloading of the mitochondrial protein ANT1, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, nucleotide biosynthesis, lysosomal biogenesis and iron homeostasis are activated. These signatures are recapitulated in yeast mutants of severe vacuolar damage. Supporting lysosomal dysfunction, the Ant1-transgenic muscles accumulate glycogens, lipofuscins and poorly processed multiple vesicle bodies. Multiple lysosomal repair and lysophagic pathways are activated. Luminal proteolytic enzymes including cathepsins are released into the cytosol, which likely contributes to imbalanced cellular proteostasis, reduced myofiber size and progressive muscle atrophy. In summary, we show an evolutionarily conserved pathway wherein mitochondrial defect can epistatically cause proteostatic damage to the lysosome thereby leading to tissue atrophy. This finding could help the better understanding of how the mitochondrial and lysosomal pathways of pathogenesis interact to cause degenerative disease.

Dataset Information

Redefining the role of the Plasmodium heme detoxification protein: From hemozoin to mitochondrial protein synthesis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets