Quantitative analyses of individual mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity

Abstract

Quantitative understanding of mitochondrial heterogeneity is necessary for elucidating the precise role of these multifaceted organelles. We demonstrate an early mechanistic role of mitochondria in initiating neoplasticity by employing our quantitative analyses of structure-function of individual mitochondria coupled with single cell transcriptomics. We demonstrate that the large Hyperfused-Mitochondrial-Networks (HMNs) promptly get converted to the heterogenous Small-Mitochondrial-Networks (SMNs) as the stem cell enriching low dose of the model carcinogen, TCDD, depolarizes mitochondria. This happens by reorganization of the HMN nodes and edges, which enriches redox tuned SMNs with distinct network complexity. This leads to establishment of transcriptomic interaction between the upregulated redox relevant mtDNA genes and the lineage specific stemness gene, KRT15, prior to cell cycle exit, and is detected only in the late-S phase of the neoplastic cell population. Consistently, high carcinogenic dose incapable of causing pronounced neoplastic stem cell enrichment fails to specifically enrich SMNs and establish the mtDNA-KRT15 transcriptomic interaction prior to cell cycle exit. The mtDNA-KRT15 modulation is confirmed in relevant tumors, while highlighting patient heterogeneity. Therefore, we propose that early enrichment of redox tuned SMNs primes neoplastic transformation by establishing interaction between mtDNA and stemness genes prior to cell cycle exit towards generating quiescent neoplastic stem cells. Our data implies that redox tuned SMNs, created by mitochondrial fission, would be sustained by tuning the balance of mitochondrial fission-fusion during neoplastic transformation. The proposed early role of mitochondria in cancer etiology is potentially relevant in designing precision strategies for cancer prevention and therapy.