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Review
. 2023 Aug 23;8(1):311.
doi: 10.1038/s41392-023-01546-w.

Mitochondrial heterogeneity in diseases

Long Chen #  1 , Mengnan Zhou #  2 , Hao Li #  3 , Delin Liu  3 , Peng Liao  3 , Yao Zong  4 , Changqing Zhang  5 , Weiguo Zou  6   7 , Junjie Gao  8   9   10
Affiliations
Review

Mitochondrial heterogeneity in diseases

Long Chen et al. Signal Transduct Target Ther. .

Abstract

As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Timeline of mitochondrial heterogeneity research. Key discoveries in the field are highlighted. Abbreviations: ncRNA noncoding RNA, mROS mitochondrial reactive oxygen species
Fig. 2
Fig. 2
Mitochondrial characteristics under different conditions. Low mitochondrial cristae density is associated with a low cellular energy supply (☹), while a high mitochondrial crista density reflects an adaptation to meet cell energy demands (☺). Mitochondrial contact with many additional organelles, such as the ER, lysosomes and lipid droplets, and the number of contacts mitochondria make with a specific organelle can vary dramatically from only a few contacts to hundreds of contacts per cell. A decrease in the number of mitochondrial connections to other organelles is typically a response to an inefficient metabolic pathway (☹), and in contrast, an increase indicates a response to an active cellular energy metabolic pathway (☺). Mitochondrial fission and fusion are the main pathways of mitochondrial morphology regulation, and under stressful environments, mitochondria are active during mitochondrial fission and produce an increased number of punctate mitochondria (☹), while mitochondrial fusion mediates the formation of mitochondrial networks that adapt to the high energy demands of cells (☺). The content of mitochondria in a cell reflects the intensity of cellular metabolism. Low mitochondrial content in cells is usually associated with low metabolic activity (☹), and high mitochondrial content is associated with high cellular metabolic activity (☺). Intercellular mitochondrial communication is extensive under physiological and pathological conditions, and a low frequency of mitochondrial communication is a response to low cellular adaptation to stressful environments (☹), and in contrast, efficient mitochondrial transfer enhances cellular adaptive capacity (☺)
Fig. 3
Fig. 3
Mitochondrial distribution during mitosis. During interphase, the mitochondrial network is evenly distributed in the cytoplasm. During prophase, the mitochondrial network is crumpled and primarily located in the perinuclear area, where punctate mitochondria are apparent. During metaphase, mitochondria move to the equatorial plane in the midline of a cell at right angles to the axis. During anaphase, mitochondria move to the opposite ends of a cell. During telophase, the mitochondrial network is re-formed and grouped at either pole of a cell. a The association of mitochondria with cytoplasmic F-actin may promote mitochondrial distribution during mitosis. b Mitochondrial delivery on microtubules may dock to actin in the cleavage furrow. c Miro-1 is required for transporting mitochondria to the plus ends of microtubules at the cleavage furrow via interaction with KIF5B. d Close association between mitochondria and both ER sheets and actin cables may promote mitochondrial distribution during mitosis. e Myo19 is localized to mitochondria and acted as a novel actin-based motor that controls mitochondrial distribution during mitosis
Fig. 4
Fig. 4
The heterogeneity of mitochondrial components. DNA component: The diversity of the mitochondrial genome arises from base-pair mismatches during the replication of the genome and base mutations after mtDNA short-patch base excision repair (BER). RNA component: Transcripts from the mitochondrial genome include rRNAs, sRNAs, CircRNAs, dsRNAs, IncRNAs, mRNAs and tRNAs. The protein component diversity of the mitochondrial proteome arises from the two main protein resources, the nucleic coding protein import pathway and the mtDNA translation pathway. In addition, mitochondrial proteins are altered via a complex posttranslational modification mechanism. The heterogeneity of mitochondrial lipids is a result of four related lipid transport pathways, including free diffusion, organelle membrane contact, lipid transport proteins and vesicular transport
Fig. 5
Fig. 5
Summary of mitochondrial functions. (1) Fusion and fission. (2) Energy metabolism. (3) Metabolism of amino acids and nucleotides. (4) Mitophagy. (5) mtDNA expression and translation. (6) mtDNA proliferation and mutation. (7) RNA posttranscriptional processing. (8) Protein quality control, degradation and modification. (9) The respiratory chain. (10) ROS clearance. (11) Signaling and the redox process. Abbreviations: MPC mitochondrial pyruvate carrier, CPT carnitine palmitoyltransferase, GLU glucose, FFA free fatty acid, Ser serine, Gly glycine, THF tetrahydrofolate, CH2-THF 5,10-methylene-THF, mtDNA mitochondrial DNA, mRNA messenger RNA, tRNA transfer RNA, ncRNA noncoding RNA, mtUPR mitochondrial unfolded protein response, HSP heat shock protein, ROS reactive oxygen species, CytC cytochrome c, GSH glutathione and GSSG glutathione oxidized
Fig. 6
Fig. 6
Comparison of mitochondrial heterogeneity in tissues. Pathways with significant differences in the mitochondrial proteome of tissue in pathological states are marked with cyan colors, and no significant differences in mitochondrial proteomic results or mitochondrial pathways with changes that were not based on mitochondrial proteomic results are marked with pink colors. Based on the research of mitochondrial-targeted transgenic mice model, we summarized the relationship between mitochondrial protein and disease pathological states, all related proteins are marked with magenta. Brain pathology state, Alzheimer’s disease (AD) and Parkinson’s disease (PD), mitochondrial function associated with (2) energy metabolism; (5) mtDNA expression and translation; (6) mtDNA proliferation and mutation; (8) protein quality control, degradation and modification; (9) the respiratory chain; (10) ROS clearance; (11) signaling and the redox process. Skeletal muscle pathology state, hypoxia and myosteatosis, mitochondrial function associated with (2) energy metabolism; (5) mtDNA expression and translation; (6) mtDNA proliferation and mutation; (8) protein quality control, degradation and modification; (9) the respiratory chain; (10), ROS clearance; (11) signaling and the redox process. Cardiovascular pathology states, heart failure (HF) and cardiomyopathy, mitochondrial function associated with (2) energy metabolism; (5) mtDNA expression and translation; (6) mtDNA proliferation and mutation; (8) protein quality control, degradation and modification; (9) the respiratory chain; (10) ROS clearance; (11) signaling and the redox process. Adipose tissue, mitochondrial function associated with (2) energy metabolism; (9) thermogenesis; (10) ROS clearance; (11) signaling and the redox process. The liver, mitochondrial function associated with (2) energy metabolism; (5) mtDNA expression and translation; (6) mtDNA proliferation and mutation; (7) RNA posttranscriptional processing; (8) protein quality control, degradation and modification; (9) the respiratory chain; (10) ROS clearance; (11) signaling and the redox process. Immune system mitochondrial function associated with (2) energy metabolism; (3) metabolism of amino acid and nucleotides; (9) the respiratory chain; (10) ROS clearance; (11) signaling and the redox process. Abbreviations: CPT1c Carnitine Palmitoyltransferase 1C, ACAT acetyl-CoA acetyltransferase 1, IDH1 isocitrate dehydrogenase 1, KGDHC α-ketoglutarate dehydrogenase complex, OSCP oligomycin sensitivity-conferring protein, NDUFB8 NADH:ubiquinone oxidoreductase subunit B8, Ndufs2 NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, HSPA9 Mortalin, Miro1 Mitochondrial Rho-GTPase, SDHA Succinate dehydrogenase complex, subunit A, PDH pyruvate dehydrogenase, BDH1 3OH-Butyrate dehydrogenase, type1, PRX-3 Peroxiredoxin 3, SOD superoxide dismutase, Nnt nicotinamide nucleotide transhydrogenase, GCLC glutamate cysteine ligase catalytic, GRP75 Glucose-regulated protein 75 kDa, HMGCS2 3-Hydroxy-3-methylglutaryl CoA synthase 2, CYP2E cytochrome P450-2E1, COX10 Cytochrome c oxidase assembly homolog 10, LONP Lon protease homolog, SLC25A42 Mitochondrial coenzyme A (CoA) transporter, UCP1 uncoupling protein 1, Ndufv2 NADH dehydrogenase [ubiquinone] Flavoprotein 2, Ndufs4 NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, SHMT2 Serine hydroxymethyl transferase 2 and MPC mitochondrial pyruvate carrier
Fig. 7
Fig. 7
Mitochondrial heterogeneity in cancer. Glycolysis, a potential protein target of key TCA cycle enzymes, is in purple. Fatty acid metabolism, a potential protein target of FAO key enzymes, is in red. Glutamate metabolism, a potential protein target of glutamine metabolism, is in orange. One-carbon metabolism, potential protein targets of one-carbon metabolism are in orange. Abbreviations: PDH pyruvate dehydrogenase, IDH isocitrate dehydrogenase, CPT1 carnitine palmitoyltransferase 1, CPT2 carnitine palmitoyltransferase 2, GLS glutaminase enzyme, GDH glutamate dehydrogenase, SHMT2 serine hydroxymethyltransferase, 2, GCS glycine cleavage system, MTHFD2 methylenetetrahydrofolate dehydrogenase, and MTHFD1L methylenetetrahydrofolate dehydrogenase 1-like
Fig. 8
Fig. 8
Heterogeneity of mitochondrial proteins in tissues. The mitochondrial protein expression data were obtained from MitoCarta 3.0 (http://www.broadinstitute.org/pubs/MitoCarta). a Mitochondrial protein expression in 14 human tissues as determined with MitoPathways. Columns represent different tissues, and rows represent the relative expression levels of different proteins. The R package (pheatmap) was used to draw the heatmap. b Mitochondrial protein expression of MitoPathways in 14 mouse tissues. Columns represent different tissues, and rows represent the relative expression levels of different proteins. The R package (pheatmap) was used to draw the heatmap. c Number of distinct proteins detected and not detected in 14 human tissues. d Number of distinct proteins detected and not detected in 14 mouse tissues. e Heatmap showing mitochondrial protein heterogeneity in 6 tissues. Maroon represents upregulated proteins in tissues under pathological conditions, and blue represents downregulated proteins in tissues under pathological conditions
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References

    1. Friedman JR, et al. Mitochondrial form and function. Nature. 2014;505:335–343. - PMC - PubMed
    1. Sierra MF, et al. Assembly of the mitochondrial system. Purification of a mitochondrial product of the ATPase. PNAS. 1973;70:3155–3159. - PMC - PubMed
    1. Pfanner N, et al. Mitochondrial proteins: from biogenesis to functional networks. Nat. Rev. Mol. Cell Biol. 2019;20:267–284. - PMC - PubMed
    1. Zorov DB, et al. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 2014;94:909–950. - PMC - PubMed
    1. Sena LA, et al. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell. 2012;48:158–167. - PMC - PubMed

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