Review Article - Journal of Cell Biology and Metabolism (2025) Volume 7, Issue 3

Mitochondrial Biogenesis and Its Impact on Cell Growth and Differentiation

Department of Molecular Genetics, Central Bioscience Institute, India.

*Corresponding Author:

Rajiv Menon
Department of Molecular Genetics
Central Bioscience Institute, India.
E-mail: rkmenon@genomeinsights.edu

Received: 03-Jun-2025, Manuscript No. AACBM-25-166663; Editor assigned: 04-Jun-2025, PreQC No. AACBM-25-1666635(PQ); Reviewed: 18-Jun-2025, QC No AACBM-25-1666635; Revised: 21-Jun-2025, Manuscript No. AACBM-25-1666635(R); Published: 28-Jun-2025, DOI:10.35841/aacbm-7.3.267

Citation: Menon R. Mitochondrial biogenesis and its impact on cell growth and differentiation. J Cell Biol Metab. 2025;7(3):267.

Introduction

Mitochondria are essential organelles known primarily for their role in producing adenosine triphosphate (ATP) through oxidative phosphorylation. Beyond their bioenergetic function, mitochondria are integral to numerous cellular processes, including calcium homeostasis, apoptosis, redox balance, and metabolite synthesis. The number and functionality of mitochondria within a cell are tightly regulated to meet the specific energy and metabolic demands of that cell type and its physiological state [1]. Mitochondrial biogenesis, the process by which new mitochondria are formed, is a critical aspect of maintaining and adapting mitochondrial function. This dynamic process plays a vital role in supporting cell growth and differentiation, with far-reaching implications in development, tissue regeneration, aging, and disease [2].

Mitochondrial biogenesis is a complex and highly coordinated process involving the synthesis of mitochondrial proteins, lipids, and mitochondrial DNA (mtDNA). Unlike most organelles, mitochondria contain their own DNA, which encodes a small number of essential proteins involved in the electron transport chain. However, the majority of mitochondrial proteins are nuclear-encoded and imported into mitochondria after translation in the cytoplasm. This necessitates close communication between the nuclear and mitochondrial genomes. The regulation of mitochondrial biogenesis is primarily mediated by nuclear transcription factors and coactivators, among which peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the most prominent [3].

PGC-1α functions as a master regulator of mitochondrial biogenesis by coactivating various transcription factors, including nuclear respiratory factors 1 and 2 (NRF1 and NRF2), which in turn upregulate the expression of mitochondrial transcription factor A (TFAM). TFAM is crucial for the replication and transcription of mtDNA. Together, these molecules initiate and sustain the expansion of mitochondrial mass and functionality. PGC-1α itself is activated by various upstream signals such as AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and calcium/calmodulin-dependent protein kinase (CaMK), which respond to energy stress, nutrient availability, and calcium fluxes. These signaling pathways ensure that mitochondrial biogenesis is closely aligned with the metabolic needs and environmental conditions of the cell [4].

During periods of rapid cell growth, such as in embryogenesis or tissue regeneration, the demand for energy and biosynthetic precursors increases substantially. In this context, mitochondrial biogenesis is essential for supplying ATP and metabolic intermediates required for macromolecule synthesis and cell cycle progression. For example, proliferating cells often exhibit increased mitochondrial content to support enhanced oxidative metabolism. The availability of ATP is critical for driving anabolic processes, while intermediates of the tricarboxylic acid (TCA) cycle serve as precursors for amino acid, lipid, and nucleotide synthesis. Moreover, the role of mitochondria in regulating redox homeostasis and apoptosis becomes increasingly important during cell proliferation, ensuring that only healthy, functionally competent cells progress through the cell cycle [5].

Mitochondrial biogenesis is not only important for cell growth but is also intimately linked to cell differentiation. Differentiation is a highly energy-dependent process that requires a profound metabolic reprogramming. Stem cells and progenitor cells typically maintain a glycolytic metabolism, which supports their pluripotency and rapid proliferation [6]. As these cells differentiate, they often switch to a more oxidative metabolism, a transition that is accompanied by increased mitochondrial biogenesis and functional maturation. For instance, during myogenesis, the differentiation of myoblasts into mature myotubes is marked by a dramatic increase in mitochondrial content and respiratory capacity. PGC-1α is upregulated during this process and drives the expression of genes necessary for mitochondrial expansion and oxidative phosphorylation [7].

Similarly, in the nervous system, neuronal differentiation requires a metabolic shift from glycolysis to oxidative metabolism, which is supported by mitochondrial biogenesis. Developing neurons increase their mitochondrial content to meet the high energy demands associated with synaptic activity, ion transport, and neurotransmitter synthesis. Disruption of mitochondrial biogenesis in this context can impair neurogenesis and contribute to neurodevelopmental disorders. In the hematopoietic system, the differentiation of hematopoietic stem cells into various blood cell lineages is also accompanied by distinct mitochondrial remodeling, further emphasizing the importance of mitochondria in lineage specification and functional maturation [8].

Mitochondrial biogenesis is equally critical in highly metabolic tissues such as the heart, liver, and brown adipose tissue. In cardiac muscle cells, the high energy demands of continuous contraction are met by abundant mitochondria, which occupy up to 40% of the cell volume. During cardiomyocyte maturation, mitochondrial biogenesis ensures the development of an efficient oxidative phosphorylation system capable of sustaining contractile function. Impaired mitochondrial biogenesis in the heart is associated with cardiomyopathies and heart failure. In brown adipose tissue, mitochondrial biogenesis supports thermogenesis by increasing the capacity for fatty acid oxidation and heat production. The thermogenic protein uncoupling protein 1 (UCP1), which dissipates the mitochondrial proton gradient to generate heat instead of ATP, is upregulated alongside mitochondrial biogenesis in response to cold exposure [9].

While mitochondrial biogenesis is essential for normal cellular function and differentiation, its dysregulation is implicated in various pathological conditions. In cancer, for instance, the role of mitochondrial biogenesis is complex and context-dependent. Some tumors exhibit increased mitochondrial biogenesis to support their metabolic needs, while others downregulate oxidative phosphorylation in favor of glycolysis, a phenomenon known as the Warburg effect. Nevertheless, many cancers retain functional mitochondria and rely on mitochondrial metabolism for growth, survival, and metastasis. Certain oncogenes and tumor suppressors, such as c-Myc and p53, can directly influence mitochondrial biogenesis, highlighting its importance in tumor biology [10].

Conclusion

In conclusion, mitochondrial biogenesis is a fundamental process that underpins cell growth, differentiation, and tissue function. By modulating energy production, redox balance, and biosynthetic capacity, mitochondria support the dynamic needs of proliferating and differentiating cells. The regulation of mitochondrial biogenesis involves an intricate network of transcriptional and signaling pathways that respond to metabolic cues and environmental stimuli. While essential for normal physiology, dysregulation of this process contributes to a wide range of diseases, from metabolic disorders to neurodegeneration and cancer. Continued research into the mechanisms controlling mitochondrial biogenesis holds significant promise for developing targeted therapies aimed at restoring mitochondrial function and improving cellular health across the lifespan.

References

1. López-Lluch G, Irusta PM, Navas P, et al. Mitochondrial biogenesis and healthy aging. Exp Gerontol. 2008;43(9):813-9.

Indexed at, Google Scholar, Cross Ref

2. Diaz F, Moraes CT. Mitochondrial biogenesis and turnover. Cell calcium. 2008;44(1):24-35.

Indexed at, Google Scholar, Cross Ref

3. Remels AH, Langen RC, Schrauwen P, et al. Regulation of mitochondrial biogenesis during myogenesis. Mol Cell Endocrinol. 2010;315(1-2):113-20.

Indexed at, Google Scholar, Cross Ref

4. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88(2):611-38.

Indexed at, Google Scholar, Cross Ref

5. Wu H, Kanatous SB, Thurmond FA, et al. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science. 2002;296(5566):349-52.

Indexed at, Google Scholar, Cross Ref

6. Kraft CS, LeMoine CM, Lyons CN, et al. Control of mitochondrial biogenesis during myogenesis. Am J Physiol Cell Physiol. 2006;290(4):C1119-27.

Indexed at, Google Scholar, Cross Ref

7. Cardanho-Ramos C, Morais VA. Mitochondrial biogenesis in neurons: how and where. Int J Mol Sci. 2021;22(23):13059.

Indexed at, Google Scholar, Cross Ref

8. Nisoli E, Carruba MO. Nitric oxide and mitochondrial biogenesis. J. Cell Sci. 2006;119(14):2855-62.

Indexed at, Google Scholar, Cross Ref

9. Piantadosi CA, Suliman HB. Redox regulation of mitochondrial biogenesis. Free Radic Biol Med. 2012;53(11):2043-53.

Indexed at, Google Scholar, Cross Ref

10. Dorn GW, Vega RB, Kelly DP. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev. 2015;29(19):1981-91.

Indexed at, Google Scholar, Cross Ref