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Review
. 2023 Feb 28;12(3):598.
doi: 10.3390/antiox12030598.

The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases

Giada Zanini  1 , Valentina Selleri  1   2 , Mara Malerba  1 , Kateryna Solodka  1   2 , Giorgia Sinigaglia  1 , Milena Nasi  3 , Anna Vittoria Mattioli  2   4 , Marcello Pinti  1
Affiliations
Review

The Role of Lonp1 on Mitochondrial Functions during Cardiovascular and Muscular Diseases

Giada Zanini et al. Antioxidants (Basel). .

Abstract

The mitochondrial protease Lonp1 is a multifunctional enzyme that regulates crucial mitochondrial functions, including the degradation of oxidized proteins, folding of imported proteins and maintenance the correct number of copies of mitochondrial DNA. A series of recent studies has put Lonp1 at the center of the stage in the homeostasis of cardiomyocytes and muscle skeletal cells. During heart development, Lonp1 allows the metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation. Knock out of Lonp1 arrests heart development and determines cardiomyocyte apoptosis. In adults, Lonp1 acts as a cardioprotective protein, as its upregulation mitigates cardiac injury by preventing the oxidative damage of proteins and lipids, and by preserving mitochondrial redox balance. In skeletal muscle, Lonp1 is crucial for cell development, as it mediates the activation of PINK1/Parkin pathway needed for proper myoblast differentiation. Skeletal muscle-specific ablation of Lonp1 in mice causes reduced muscle fiber size and strength due to the accumulation of mitochondrial-retained protein in muscle. Lonp1 expression and activity decline with age in different tissues, including skeletal muscle, and are associated with a functional decline and structural impairment of muscle fibers. Aerobic exercise increases unfolded protein response markers including Lonp1 in the skeletal muscle of aged animals and is associated with muscle functional recovery. Finally, mutations of Lonp1 cause a syndrome named CODAS (Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies) characterized by the impaired development of multiple organs and tissues, including myocytes. CODAS patients show hypotonia and ptosis, indicative of skeletal muscle reduced performance. Overall, this body of observations points Lonp1 as a crucial regulator of mitochondrial functions in the heart and in skeletal muscle.

Keywords: Lon protease; UPRmt; heart dysfunction; sarcopenia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mitochondrial functions of Lonp1 in myocytes and cardiomyocytes. In mitochondria, Lonp1 (i) regulates mitophagy through Pink1 degradation; (ii) regulates protein turnover by degrading misfolded or damage proteins; (iii) modulates mitochondrial dynamics through the action of Mfn1 and Mfn2, which promote fusion, and Drp1, which promotes fission; (iv) regulates stress response by preserving mtDNA integrity and modulating ROS production; (v) modulates respiratory chain complexes activity.
Figure 2
Figure 2
Age-related Lonp1 effects on cardiomyocytes and myocytes. In the mitochondria of cardiomyocytes and myocytes, Lonp1 plays an important role in counteracting ROS production and maintaining mitochondrial homeostasis through efficient mitophagy, DNA repair system, and UPRmt response. During aging, Lonp1 levels decrease, leading to higher ROS levels, impaired mitophagy, release of damaged mtDNA and fragmented dsDNA, and impaired UPRmt response, a series of effects that can favour myocyte damage in skeletal muscle and sarcopenia.
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