Mitochondria are unique organelles that are essential for a variety of cellular functions, including ATP synthesis, calcium homeostasis, cell survival, and cell death. Mitochondria are an important source of energy production in eukaryotic cells and also play an important role in the production of lipids, nucleic acids, and amino acids. Mitochondria are vulnerable to oxidative stress. The main sources of ROS synthesis in cells are mitochondria and NADPH oxidase (NOX). In mitochondria, ROS is produced during the respiratory chain, while in NOX it is produced along the membranes of neutrophils and phagosomes. Under certain conditions, the production of free radicals such as OH●- , and O2 ●- will result in vulnerabilities. ROS which is produced by mitochondria has many targets, including lipids, proteins, DNA, RNA, and mitochondrial DNA (mtDNA), which become a vulnerable target for oxidative stress due to the lack of histones. Impaired mtDNA and disrupted mitochondrial genome integrity have main roles in the development of severe early-onset and chronic aging-related diseases. It is becoming increasingly clear that long-term, tiny mtDNA damage is not only related to the aging process but may also be closely related to diabetes and nephropathies. Mitochondrial dysfunction has the main role in renal diseases. Epigenetic alterations and interactions between mtDNA, ROS, and inflammatory factors affect nephrons. Alterations of mtDNA affect the development and progression of chronic kidney disease. Alteration of mtDNA also has a significant role in nephropathies monitoring. Evidence suggests that modification in several mtDNA copies in the circulation and urine reflects mitochondrial dysfunction and kidney disease severity. This review will describe mitochondrial antioxidants in nephropathies therapy. Targeted mitochondrial antioxidants will become a new insight in nephropathies therapy. mtDNA can also be a therapeutic target.